KR20110023895A - Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof - Google Patents

Abstract

The present application is directed to novel 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethylindole derivatives, methods for their preparation, individual or combination uses for the treatment and / or prevention of diseases, treatment and / or prevention of diseases. And to their use in the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular diseases, in particular.

Description

Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indole, and their use {SUBSTITUTED 7-SULFANYLMETHYL, 7-SULFINYLMETHYL AND 7-SULFONYLMETHYL INDOLES AND USE THEREOF}

The present application provides novel 7-sulfanylmethyl-, 7-sulfinylmethyl- and 7-sulfonylmethylindole derivatives, methods for their preparation, their use for the treatment and / or prophylaxis of diseases, alone or in combination, for the treatment of diseases. And / or use thereof in the manufacture of a medicament for the prevention, in particular for the treatment and / or prevention of cardiovascular disorders.

Aldosterone maintains body fluid and electrolyte homeostasis by promoting sodium retention and potassium secretion in the epithelium of distal identity, contributing to maintaining extracellular volume and thus playing an important part in regulating blood pressure. In addition, aldosterone has a direct effect on the structure and function of the heart and vascular system, but its underlying mechanism has not been fully described (RE Booth, JP Johnson, JD Stockand, Adv. Physiol.Educ. 26 (1), 8-20 (2002)].

Aldosterone is a steroid hormone that is formed in the adrenal cortex. Its production is regulated indirectly depending very much on the blood flow of the kidneys. Any decrease in renal blood flow causes the kidney to release the enzyme renin into the circulating blood. This in turn activates the formation of angiotensin II, which on the one hand exhibits a contractile effect on the arterial vessels, on the other hand, stimulates the formation of aldosterone in the adrenal cortex. Thus, the kidney acts as a blood pressure sensor, and thus an indirect volume sensor in the circulating blood, through the Lenin-Angiotensin-Aldosterone system, on the one hand to increase blood pressure (Angiotensin II effect), and on the other hand sodium and By increasing the resorption of water to rebalance the state of charge of the vasculature (the aldosterone effect), it copes with the crucial loss of volume.

Such regulatory systems can be pathologically impaired in a variety of ways. Thus, chronic reduction of renal blood flow results in chronic excessive release of aldosterone (eg, as a result of heart failure and consequent venous blood congestion). Thereafter, the blood volume expands, thereby supplying excess volume to the heart, which increases cardiac weakness. As a result, with congestion of blood in the lungs, edema formation, ascites and pleural effusion may appear in short breaths and limbs, and renal blood flow is further lowered. In addition, excessive aldosterone effects result in a decrease in potassium concentration in blood and extracellular fluid. Otherwise in already injured myocardium, deviations below the critical minimum level can lead to cardiac arrhythmias with fatal consequences. This may be one of the main causes of sudden cardiac death, which is common in heart failure patients.

In addition, aldosterone is believed to be responsible for the numerous myocardial remodeling processes typically observed in heart failure. Thus, hyperaldosteronemia is an important factor in the pathogenesis and prognosis of heart failure, which can be originally induced by various types of injury, such as myocardial infarction, myocardial inflammation or hypertension. This presumption is supported by the fact that the overall survival has been significantly reduced in extensive clinical studies using aldosterone antagonists for patients with chronic heart failure and acute myocardial infarction symptoms (B. Pitt, F. Zannad, WJ Remme et. al., N. Engl. J. Med. 341, 709-717 (1999); B. Pitt, W. Remme, F. Zannad et al., N. Engl. J. Med. 348, 1309-1321 (2003)]. This could be particularly achieved by reducing the occurrence of sudden cardiac death.

Recent studies have shown that quite a few patients suffering from essential hypertension also have a so-called hyperkalemia variant of primary hyperaldosteronemia (occurs in less than 11% of all hypertensions, see L. Seiler and M). Reincke, Der Aldosteron-Renin-Quotient bei sekundarer Hypertonie, Herz 28, 686-691 (2003)]. The best diagnostic method for hyperkalemia is the aldosterone / renin ratio of the corresponding plasma concentration, so the relative rise of aldosterone over the renin plasma concentration can also be diagnosed and eventually treated. For this reason, hyperaldosteronemia diagnosed with essential hypertension is the starting point for causal and prophylactically valuable therapies.

Pathological conditions where damage is found in the hormone-producing cells of the adrenal gland itself, or whose number or mass is increased through hyperplasia or proliferation, are much less common than hyperaldosteronemia of the type described above. Adenoma or diffuse hyperplasia of the adrenal cortex is the most common cause of primary hyperaldosteronemia called Conn syndrome, the main symptoms of which are hypertension and hypokalemia. In addition to surgically removing the affected tissue, medical therapy with aldosterone antagonists is also a priority. (H.A. Kuhn and J. Schirmeister (Editors), Innere Medizin, 4th edition, Springer Verlag, Berlin, 1982).

Another pathological condition, typically associated with elevated plasma aldosterone levels, is progressive cirrhosis. In this case, the cause of aldosterone elevation is mainly limited aldosterone destruction due to impaired liver function. Volume overload, edema and hypokalemia are typical results, which can be successfully alleviated by aldosterone antagonists in clinical trials.

The effect of aldosterone is modulated by mineralocorticoid receptors with intracellular positions in target cells. The receptors closely related to the mineralocorticoid receptors are glucocorticoid receptors that are mediated through the activity of glucocorticoids (eg cortisone, cortisol or corticosterone). Mineralocorticoid receptors bind not only aldosterone but also endogenous glucocorticoids (Funder JW. Hypertension. 47, 634-635 (2006)). This interaction of mineralocorticoid receptors and glucocorticoids is likewise important in the pathophysiology of heart disorders but is believed to play an unacknowledged role in most cases. In addition, interactions between mineralocorticoids and glucocorticoid receptors are proposed, for example in the form of heterodimer formations that may be associated with the development of cardiovascular disorders (Liu W, Wang J, Sauter NK, Pearce D). Proc Natl Acad Sci US A. 92, 12480-12484 (1995)].

The aldosterone antagonists used so far have been aldosterone itself with a basic steroid structure. Such steroidal antagonists have limited utility due to their interaction with receptors of other steroid hormones and in some cases cause significant side effects such as gynecomastia and erectile dysfunction and lead to discontinuation of the therapy (MA Zaman, S. Oparil, DA Calhoun, Nature Rev. Drug Disc. 1, 621-636 (2002)].

In particular, the identification of potent non-steroidal mineralocorticoid receptor antagonists with improved selectivity for androgen (testosterone) and progesterone receptors offers the possibility of achieving characteristic therapeutic advantages (MJ Meyers and X. Hu, Expert Opin. Ther. Patents 17 (1), 17-23 (2007).

Accordingly, it is an object of the present invention to serve as a potent mineralocorticoid receptor antagonist that is selective for androgen (testosterone) and progesterone receptors and exhibit an improved profile of side effects compared to compounds known in the prior art, and thus disorders, in particular It is to provide a novel compound that can be used in the treatment of cardiovascular disorders.

Indol-3-yl (phenyl) acetic acid derivatives are disclosed in WO 97/43260 as endothelin receptor antagonists, and α-amino (indol-3-yl) acetic acid derivatives with antidiabetic effects are disclosed in WO 90/05721. WO 2004/067529, WO 2005/092854 and in M. G. Bell, J. Med. Chem. 2007, 50 (26), 6443-6445, describe various indole derivatives substituted at position 3 as modulators of steroid hormone receptors. WO 2007/062994 and WO 2005/118539 claim 3- (3-amino-1-arylpropyl) indole for the treatment of depression and anxiety conditions. WO 2007/040166 claims a fused pyrrole derivative as a glucocorticoid receptor modulator with anti-inflammatory and antidiabetic effects. WO 2007/070892 and WO 2008/019357 describe substituted indole for the treatment of anxiety, pain, inflammatory disorders and cognitive impairment. WO 2008/157740 describes various substituted indoles, in particular for the treatment of pain and inflammatory disorders. 3- (indol-3-yl) -3-phenylpropionitrile derivatives are described in particular in US 2 752 358, US 2 765 320 and US 2 778 819. The preparation of 2-unsubstituted indole is disclosed in WO 98/06725 and US 5,808,064. The preparation of 2- (indol-3-yl) -2-phenylethanol derivatives is described in particular in M.L. Kantam et al., Tetrahedron Lett. 2006, 47 (35), 6213-6216.

The present invention relates to compounds of formula (I) and salts, solvates and solvates thereof.

<Formula I>

Where

A is -S-, -S (= O)-or -S (= O) _2- ,

R ¹ is (C ₁ -C ₄ ) -alkyl or cyclopropyl,

R ² is hydrogen, fluorine or chlorine,

R ³ is hydrogen, fluorine, chlorine or methyl,

R ⁴ is hydrogen or fluorine,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

D is -CH _2- , -O-, -CH ₂ -CH ₂ -or -CH ₂ -O-,

R ⁶ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,

Wherein (C ₁ -C ₄ ) -alkyl may be substituted with one to three substituents independently selected from the group of fluorine, trifluoromethyl, hydroxy and cyano,

Wherein (C ₃ -C ₆ ) -cycloalkyl can be substituted with one to three substituents independently selected from the group of fluorine, hydroxy and cyano,

R ⁷ is hydrogen, halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl or (C ₁ -C ₄ ) -alkoxy,

R ⁸ is hydrogen, halogen, methyl or trifluoromethyl,

R ⁹ is phenyl, naphthyl or 5-10 membered heteroaryl,

Wherein phenyl, naphthyl and 5- to 10-membered heteroaryl are halogen, cyano, (C ₁ -C ₄ ) -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -May be substituted with 1 to 3 substituents independently selected from the group of alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio, or

Wherein the two substituents bonded to adjacent carbon atoms of the phenyl ring together may be represented by the formulas —O—CH ₂ —O—, —O—CHF—O—, —O—CF ₂ —O—, —O—CH ₂ —CH Form a group of ₂ -O- or -O-CF ₂ -CF ₂ -O-,

R ¹⁰ is (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl,

Wherein (C ₁ -C ₆ ) -alkyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy and cyano and ,

Wherein (C ₃ -C ₇ ) -cycloalkyl can be substituted with one to three substituents independently selected from the group of fluorine, hydroxy and cyano,

Wherein phenyl is halogen, cyano, (C ₁ -C ₄ ) -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy, fluoromethoxy, difluorometh May be substituted with 1 to 3 substituents independently selected from the group of oxy, trifluoromethoxy and trifluoromethylthio,

R ¹¹ is hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl.

The compounds of the present invention are included in formula (I) and the compounds of formula (I), and salts, solvates, and solvates of the salts thereof, unless the compounds mentioned thereafter are already salts, solvates, and solvates of the salts. Of a compound having a chemical formula, and salts, solvates, and solvates of the salts thereof, and compounds included in Formula I and hereinafter referred to as exemplary embodiments, and salts, solvates, and salts of the salts Solvate.

The compounds of the present invention may exist in stereoisomeric forms (enantiomers, diastereomers), depending on their structure. Accordingly, the present invention relates to enantiomers or diastereomers and mixtures thereof. Stereoisomeric components may be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

Where the compounds of the present invention may exist in tautomeric forms, the present invention includes all tautomeric forms.

Preferred salts for the purposes of the present invention are physiologically acceptable salts of the compounds of the present invention. Although not per se suitable for pharmaceutical use, salts which can be used, for example, for the isolation or purification of the compounds of the invention are also included.

Physiologically acceptable salts of the compounds of the present invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene Salts of disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of the present invention include salts of conventional bases, such as, preferably, alkali metal salts (eg sodium and potassium salts), alkaline earth metal salts (eg calcium and magnesium salts) And ammonia or organic amines having 1 to 16 carbon atoms (such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dish) Ammonium salts derived from clohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine).

For the purposes of the present invention shows a solvate form of a compound of the invention which is coordinated with the solvent molecules in the solid or liquid state form a complex. Hydrates are an unusual form of solvates coordinated in water. In the present invention, hydrates are preferred solvates.

The invention further includes prodrugs of the compounds of the invention. The term “prodrug”, by itself, includes compounds which may be biologically active or inactive but are converted (eg, by metabolism or hydrolysis) to a compound of the invention during the time of staying in the body.

In the context of the present invention, substituents have the following meanings unless otherwise specified:

Alkyl refers to a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms in the context of the present invention. Preference is given to linear or branched alkyl radicals having 1 to 4 carbon atoms. By way of example, mention may be made of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

Cycloalkyl refers to saturated monocyclic carbocycles having 3 to 7 or 3 to 6 ring carbon atoms in the context of the present invention. By way of example, preference may be given to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkoxy refers to a linear or branched alkoxy radical having 1 to 4 carbon atoms in the context of the present invention. By way of example, mention may be made of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Heteroaryl includes up to 3 identical or different ring heteroatoms from N, O and / or S in the context of the present invention and is a total of 5 to 10 ring atoms, connected via a ring carbon atom or, if appropriate, a ring nitrogen atom Monocyclic or where appropriate bicyclic aromatic heterocycle (heteroaromatic system). Examples are furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyri Dazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyl Mention may be made of lidinyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a] pyridinyl and pyrazolo [3,4-b] pyridinyl.

Halogen includes fluorine, chlorine, bromine and iodine in the context of the present invention. Fluorine, chlorine and bromine are preferred, and fluorine and chlorine are particularly preferred.

In the formulas of the possible groups for R ⁵ , R ⁹ , R ¹⁰ and R ¹¹ , the end points of the lines with the symbols #, *, ## or ### do not represent carbon atoms or CH ₂ groups, but are specified in each case and R ⁵ , R ⁹ , R ¹⁰ and R ¹¹ each form part of a bond with the atom to which it is attached.

When a radical in a compound of the present invention is substituted, the radical may be substituted one or more times unless otherwise stated. In the context of the present invention, all one or more radicals have meanings independent of each other. Preference is given to substitution by one or two identical or different substituents. Very particular preference is given to substitution by one substituent.

In the context of the present invention,

A is -S-, -S (= O)-or -S (= O) _2- ,

R ¹ is (C ₁ -C ₄ ) -alkyl or cyclopropyl,

R ² is hydrogen, fluorine or chlorine,

R ³ is hydrogen, fluorine, chlorine or methyl,

R ⁴ is hydrogen or fluorine,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

D is -CH _2- , -O-, -CH ₂ -CH ₂ -or -CH ₂ -O-,

R ⁶ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,

Wherein (C ₁ -C ₄ ) -alkyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, trifluoromethyl, hydroxy and cyano,

Wherein (C ₃ -C ₆ ) -cycloalkyl can be substituted with 1 to 3 substituents independently selected from the group of fluorine, hydroxy and cyano,

R ⁷ is hydrogen, halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl or (C ₁ -C ₄ ) -alkoxy,

R ⁸ is hydrogen, halogen, methyl or trifluoromethyl,

R ⁹ is phenyl, naphthyl or 5-10 membered heteroaryl,

Wherein phenyl, naphthyl and 5- to 10-membered heteroaryl are halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy and tri May be substituted with 1 to 3 substituents independently selected from the group of fluoromethylthio, or

Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring together represent, -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-, -O-CH _2- Form a group of CH ₂ -O- or -O-CF ₂ -CF ₂ -O-,

R ¹⁰ is (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl,

Wherein (C ₁ -C ₆ ) -alkyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, trifluoromethyl, hydroxy and cyano,

Wherein (C ₃ -C ₇ ) -cycloalkyl can be substituted with 1 to 3 substituents independently selected from the group of fluorine, hydroxy and cyano,

Wherein phenyl is independently from each other from the group of halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy and trifluoromethylthio May be substituted with 1 to 3 substituents selected,

R ¹¹ is hydrogen, methyl, ethyl or trifluoromethyl,

Preferred are the compounds of formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O)-or -S (= O) _2- ,

R ¹ is methyl or ethyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl, naphthyl or benzothienyl,

Wherein phenyl, naphthyl and benzothienyl may be substituted with one to three substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl and methoxy, or

Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring form a group of the formula -O-CH ₂ -O- or -O-CF ₂ -O-,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2 -Yl, 1-hydroxycycloprop-2-yl or phenyl,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2- One and 1-hydroxycycloprop-2-yl may be substituted with one or two fluorine substituents,

Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,

R ¹¹ is hydrogen,

Preferred are the compounds of formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O)-or -S (= O) _2- ,

R ¹ is methyl or ethyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl, naphthyl or benzothienyl,

Wherein phenyl, naphthyl and benzothienyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2 -Yl, 1-hydroxycycloprop-2-yl or phenyl,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2- One and 1-hydroxycycloprop-2-yl may be substituted with one or two fluorine substituents,

Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,

R ¹¹ is hydrogen,

Preferred are the compounds of formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O)-or -S (= O) _2- ,

R ¹ is methyl or ethyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

D is -CH ₂ -or -CH ₂ -O-,

R ⁶ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,

Wherein (C ₁ -C ₄ ) -alkyl and (C ₃ -C ₆ ) -cycloalkyl may be substituted with one or two fluorine substituents,

Wherein (C ₁ -C ₄ ) -alkyl may be substituted with a substituent selected from the group of hydroxy and cyano,

Wherein (C ₃ -C ₆ ) -cycloalkyl can be substituted with a substituent selected from the group of hydroxy and cyano,

R ⁷ is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R ⁸ is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R ⁹ is phenyl, naphthyl or benzothienyl,

Wherein phenyl, naphthyl and benzothienyl may be substituted with one to three substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl and methoxy, or

Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring form a group of the formula -O-CH ₂ -O- or -O-CF ₂ -O-,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, (C ₃ -C ₇ ) -cycloalkyl or phenyl ego,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl and (C ₃ -C ₇ ) -cycloalkyl are 1 or Can be substituted with two fluorine substituents,

Wherein (C ₃ -C ₇ ) -cycloalkyl can be substituted with a substituent selected from the group of hydroxy and cyano,

Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,

R ¹¹ is methyl or ethyl,

Preferred are the compounds of formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O)-or -S (= O) _2- ,

R ¹ is methyl or ethyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

D is -CH ₂ -or -CH ₂ -O-,

R ⁶ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,

Wherein (C ₁ -C ₄ ) -alkyl and (C ₃ -C ₆ ) -cycloalkyl may be substituted with one or two fluorine substituents,

Wherein (C ₁ -C ₄ ) -alkyl may be substituted with a substituent selected from the group of hydroxy and cyano,

Wherein (C ₃ -C ₆ ) -cycloalkyl can be substituted with a substituent selected from the group of hydroxy and cyano,

R ⁷ is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R ⁸ is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,

R ⁹ is phenyl, naphthyl or benzothienyl,

Wherein phenyl, naphthyl and benzothienyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, (C ₃ -C ₇ ) -cycloalkyl or phenyl ego,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl and (C ₃ -C ₇ ) -cycloalkyl are 1 or Can be substituted with two fluorine substituents,

Wherein (C ₃ -C ₇ ) -cycloalkyl can be substituted with a substituent selected from the group of hydroxy and cyano,

Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,

R ¹¹ is methyl or ethyl,

Preferred are the compounds of formula (I) and salts, solvates and solvates thereof.

In the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

의 기이고,R ⁹ is chemical formula

Is the flag of,

Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,

R ¹² is fluorine, chlorine, methyl and trifluoromethyl,

R ¹³ is hydrogen, fluorine or chlorine,

R ¹⁴ is hydrogen, fluorine or chlorine,

R ¹⁵ is hydrogen, fluorine or chlorine,

Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,

R ¹⁰ is cyclopropyl,

Wherein cyclopropyl may be substituted with one or two fluorine substituents,

Wherein cyclopropyl may be substituted with a cyano substituent,

R ¹¹ is methyl,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl or ethyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl or benzothienyl,

Wherein phenyl and benzothienyl may be substituted with one or two substituents independently selected from each other from the group of fluorine, chlorine, methyl and trifluoromethyl,

R ¹⁰ is cyclopropyl,

Wherein cyclopropyl may be substituted with one or two fluorine substituents,

Wherein cyclopropyl may be substituted with a cyano substituent,

R ¹¹ is methyl,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl or ethyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

D is -CH _2- ,

R ⁶ is methyl, ethyl or cyclopropyl,

R ⁷ is hydrogen, fluorine, chlorine or methyl,

R ⁸ is hydrogen, fluorine or chlorine,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

의 기이고,R ⁹ is chemical formula

Is the flag of,

Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,

R ¹² is fluorine, chlorine, methyl and trifluoromethyl,

R ¹³ is hydrogen, fluorine or chlorine,

R ¹⁴ is hydrogen, fluorine or chlorine,

R ¹⁵ is hydrogen, fluorine or chlorine,

Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-2-methyleth-2-yl or 1-cyanoprop-3-yl,

R ¹¹ is methyl or ethyl,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

의 기이고,R ⁹ is chemical formula

Is the flag of,

Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,

R ¹² is fluorine, chlorine, methyl and trifluoromethyl,

R ¹³ is hydrogen, fluorine or chlorine,

R ¹⁴ is hydrogen, fluorine or chlorine,

R ¹⁵ is hydrogen, fluorine or chlorine,

Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,

의 기이고,R ¹⁰ is

Is the flag of,

Where ## is the attachment point for -CR ⁹ R ¹¹ ,

R ¹⁶ is fluorine or chlorine,

R ¹¹ is hydrogen,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl or ethyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl or benzothienyl,

Wherein phenyl and benzothienyl may be substituted with one or two substituents independently selected from each other from the group of fluorine, chlorine, methyl and trifluoromethyl,

R ¹⁰ is phenyl,

Wherein phenyl may be substituted with a substituent selected from the group of fluorine and chlorine,

R ¹¹ is hydrogen,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl or benzothienyl,

Wherein phenyl and benzothienyl may be substituted with one or two substituents independently selected from each other from the group of fluorine, chlorine, methyl and trifluoromethyl,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-2-methyleth-2-yl or 1-cyanoprop-3-yl,

R ¹¹ is hydrogen,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

의 기이고,R ⁹ is chemical formula

Is the flag of,

Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,

R ¹² is fluorine, chlorine, methyl and trifluoromethyl,

R ¹³ is hydrogen, fluorine or chlorine,

R ¹⁴ is hydrogen, fluorine or chlorine,

R ¹⁵ is hydrogen, fluorine or chlorine,

Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,

R ¹⁰ is cyclopropyl,

Wherein cyclopropyl may be substituted with a cyano substituent, or

Wherein cyclopropyl may be substituted with one or two fluorine substituents,

R ¹¹ is hydrogen,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

의 기이고,R ⁹ is chemical formula

Is the flag of,

Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,

R ¹² is fluorine, chlorine, methyl and trifluoromethyl,

R ¹³ is hydrogen, fluorine or chlorine,

R ¹⁴ is hydrogen, fluorine or chlorine,

R ¹⁵ is hydrogen, fluorine or chlorine,

Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,

의 기이고,R ¹⁰ is

Is the flag of,

Where ### is the attachment point for -CR ⁹ R ¹¹ ,

R ¹¹ is hydrogen,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also, in the context of the present invention

A is -S (= O) _2- ,

R ¹ is methyl,

R ² is hydrogen or fluorine,

R ³ is hydrogen or fluorine,

R ⁴ is hydrogen,

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

의 기이고,R ⁹ is chemical formula

Is the flag of,

Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,

R ¹² is fluorine, chlorine, methyl and trifluoromethyl,

R ¹³ is hydrogen, fluorine or chlorine,

R ¹⁴ is hydrogen, fluorine or chlorine,

R ¹⁵ is hydrogen, fluorine or chlorine,

Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,

의 기이고,R ¹⁰ is

Is the flag of,

Where ### is the attachment point for -CR ⁹ R ¹¹ ,

R ¹¹ is hydrogen,

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates thereof.

Also preferred are compounds of formula I, wherein A is -S-, -S (= 0)-or -S (= 0) ₂ -in the context of the present invention.

Also preferred are compounds of formula I, wherein A is -S (= 0)-in the context of the present invention.

Also preferred are compounds of formula I, wherein A is -S (= 0) ₂ -in the context of the present invention.

Also, in the context of the present invention

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl, naphthyl or 5-10 membered heteroaryl,

Wherein phenyl, naphthyl and 5- to 10-membered heteroaryl are halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy and tri May be substituted with 1 to 3 substituents independently selected from the group of fluoromethylthio,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-2-methyleth-2-yl or 1-cyanoprop-3-yl,

Preferred are compounds of formula I, wherein R ¹¹ is hydrogen.

Also, in the context of the present invention

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl, naphthyl or benzothienyl,

Wherein phenyl, naphthyl and benzothienyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2 -Yl, 1-hydroxycycloprop-2-yl or phenyl,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2- One and 1-hydroxycycloprop-2-yl may be substituted with one or two fluorine substituents,

Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,

Preferred are compounds of formula I, wherein R ¹¹ is hydrogen.

Also, in the context of the present invention

의 기이고,R ⁵ is a chemical formula

Is the flag of,

Where # is the point of attachment to the indole,

R ⁹ is phenyl, naphthyl or benzothienyl,

Wherein phenyl, naphthyl and benzothienyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,

R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2 -Yl, 1-hydroxycycloprop-2-yl or phenyl,

Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2- One and 1-hydroxycycloprop-2-yl may be substituted with one or two fluorine substituents,

Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,

Preferred are compounds of formula I, wherein R ¹¹ is methyl.

Also preferred are compounds of formula I, wherein R ¹¹ is hydrogen in the context of the present invention.

Also preferred are compounds of formula I, wherein R ¹¹ is methyl in the context of the present invention.

Also preferred are compounds of formula I, wherein R ¹¹ is methyl, ethyl or cyclopropyl in the context of the present invention.

Also preferred are compounds of formula I, wherein R ¹⁰ is cyclopropyl in the context of the present invention.

Also, in the context of the present invention

R ¹⁰ is cyclopropyl,

Wherein cyclopropyl may be substituted with a cyano substituent, or

Preference is given here to compounds of the formula (I) in which cyclopropyl can be substituted with one or two fluorine substituents.

Also, in the context of the present invention

의 기이고,R ¹⁰ is

Is the flag of,

Preference is given here to compounds of the formula (I) in which ### is the point of attachment to -CR ⁹ R ¹¹ .

Also, in the context of the present invention

R ¹⁰ is phenyl,

Preference is given here to compounds of the formula (I) in which phenyl can be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl.

Also, in the context of the present invention

의 기이고,R ¹⁰ is

Is the flag of,

Where ## is the attachment point for -CR ⁹ R ¹¹ ,

Preferred are compounds of formula I, wherein R ¹⁶ is fluorine or chlorine.

Also, in the context of the present invention

의 기이고,R ⁹ is chemical formula

Is the flag of,

Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,

R ¹² is fluorine, chlorine, methyl and trifluoromethyl,

R ¹³ is hydrogen, fluorine or chlorine,

R ¹⁴ is hydrogen, fluorine or chlorine,

R ¹⁵ is hydrogen, fluorine or chlorine,

Provided that compounds of formula I are preferred, wherein at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen.

Also, in the context of the present invention

R ⁹ is phenyl, naphthyl or benzothienyl,

Wherein phenyl, naphthyl and benzothienyl can be substituted with one to three substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl This is preferred.

Also, in the context of the present invention

R ⁹ is phenyl or benzothienyl,

Preference is given here to compounds of the formula (I) in which phenyl and benzothienyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, methyl and trifluoromethyl.

The definition of radicals specifically indicated in each combination or preferred combination of radicals is replaced by the definition of radicals in other combinations, if desired, irrespective of the particular combination indicated for that radical.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

The present invention further

[A] The indole derivative of formula (I-1) is reacted with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, in an inert solvent to give a compound of formula (I-2)

<Formula I-1>

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated above in each case)

<Formula I-2>

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated above in each case), or

[B] reacting an indole derivative of formula (I-1) with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, in an inert solvent to obtain a compound of formula (I-3)

<Formula I-1>

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated above in each case)

<Formula I-3>

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated above in each case), or

[C] The indole derivative of the formula (II) is oxidized in an inert solvent with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, to give a compound of the formula (II-2), and then the latter is a suitable acid and / or Reacting with a compound of formula XI in the presence of a Lewis acid to give a compound of formula I-2

<Formula II>

(Wherein R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above in each case)

<Formula II-2>

(Wherein R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above in each case)

(XI)

(Wherein R ⁵ has the meaning indicated above), or

[D] The indole derivative of the formula (II) is oxidized in an inert solvent with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, to give a compound of the formula (II-3), and then the latter in a inert solvent Reacting with a compound of formula XI in the presence of a Lewis acid to give a compound of formula I-3

<Formula II>

(Wherein R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above in each case)

<Formula II-3>

(Wherein R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above in each case)

(XI)

(Wherein R ⁵ has the meaning indicated above),

Where appropriate, the resulting compounds of formula (I-2) or (I-3) are separated into their enantiomers and / or diastereomers by methods known to those skilled in the art and / or (i) solvents and / or (ii) bases Or converting solvates, salts and / or solvates of the salts thereof with an acid, to a process for the preparation of the compounds of formula (I) of the invention.

The compounds of formulas I-1, I-2 and I-3 together form a group of compounds of formula I of the present invention.

Suitable solvents for reactions (I-1) → (I-2) or (I-3) and (II) → (II-2) or (II-3) are all organic solvents which are inert under the reaction conditions. Examples include ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, alcohols such as Methanol, ethanol, isopropanol and tert-butanol, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene, or other solvents Such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP), acetonitrile or pyridine. It is likewise possible to use mixtures of the solvents described above. Dichloromethane is preferably used.

Suitable oxidizing agents for reactions (I-1) → (I-2) or (I-3) and (II) → (II-2) or (II-3) are organic oxidizing agents such as tert-butyl peroxide, meta -Chloroperbenzoic acid, and inorganic oxidizing agents such as hydrogen peroxide, oxone (OXONE, CAS-RN 37222-66-5), or tetrabutylammonium perruthenate (TPAP / NMO) in combination with N-methylmorpholine oxide. Meta-chloroperbenzoic acid is preferably used.

The oxidizing agent is 1 to 1.2 mol, preferably 1 to 1.05, based on 1 mol of the compound of formula I-1 or II in the case of reactions (I-1) → (I-2) and (II) → (II-2) It can be used in an amount of mol.

The oxidizing agent is 2 to 4 mol, preferably 2 to 2.2, based on 1 mol of the compound of formula (I-1) or (II-3) for reactions (I-1) → (I-3) and (II) → (II-3) It can be used in an amount of mol.

Reactions (I-1) → (I-2) or (I-3) and (II) → (II-2) or (II-3) generally range from -78 ° C to + 50 ° C, preferably- It is carried out at temperatures in the range from 20 ° C. to + 50 ° C., in particular in the range from 0 ° C. to + 30 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (for example in the range from 0.5 to 5 bar). Generally it is carried out under atmospheric pressure.

Suitable solvents for process steps (II-2) + (XI)-(I-2) and (II-3) + (XI)-(I-3) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, primary alcohols such as methanol, ethanol, n-propanol And n-butanol, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane and chlorobenzene, or bipolar aprotic solvents such as dimethyl Formamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Dichloromethane, 1,2-dichloroethane and toluene are preferably used.

Suitable acids for process steps (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) are acetic acid, trifluoroacetic acid, sulfuric acid, para-toluenesulfonic acid, Camphorsulfonic acid, methanesulfonic acid or hydrochloric acid. Trifluoroacetic acid is preferably used. The acid in this reaction can be used in an amount of 0.9 to 2.0 mol, preferably 1 to 1.2 mol, based on 1 mol of the compound of formula II.

Suitable Lewis acids for process steps (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) include boron trifluoride-diethyl ether complex, cerium ammonium nitrate ( IV) (CAN), tin (II) chloride, lithium perchlorate, zinc (II) chloride, indium (III) chloride or indium (III) bromide. Indium (III) chloride is preferably used. Lewis acids in this reaction can be used in amounts of 0.2 to 2.0 mol, preferably 0.7 to 1.2 mol, based on 1 mol of the compound of formula II.

Reactions (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) are preferred if appropriate and also for trifluoroacetic acid and indium (III) chloride Preferably a mixture of acid and Lewis acid. Acids and Lewis acids may be used in ratios of 1:99 to 99: 1, preferably 2: 1 to 4: 3.

The reaction is generally at temperatures ranging from -40 ° C. to + 40 ° C., preferably 0 ° C. to + 30 ° C. when acid is used, and generally + 20 ° C. to + 150 ° C., preferably +40 when Lewis acid is used. It is carried out at a temperature in the range from 0 ° C to + 100 ° C.

The process described is illustrated by the following scheme:

<Scheme 1>

(a): 1 equivalent of meta-chloroperbenzoic acid, 0 ° C. → RT, CH ₂ Cl ₂ ; b): 2.2 equivalents of meta-chloroperbenzoic acid, 0 ° C. → RT, CH ₂ Cl ₂ ].

<Reaction Scheme 12>

(a): 2 equivalents of meta-chloroperbenzoic acid, CH ₂ Cl ₂ , 0 ° C. → RT; b): trifluoroacetic acid, CH ₂ Cl ₂ , RT].

<Reaction Scheme 13>

(a): 1 equivalent of meta-chloroperbenzoic acid, CH ₂ Cl ₂ , 0 ° C. → RT; b): trifluoroacetic acid, CH ₂ Cl ₂ , RT].

Alternatively, reactions (II-2) → (I-2) and (II-3) → (I-3) can also be carried out using the following acetate (XI-A) (see Scheme 14).

<Formula XI-A>

(Wherein R ⁵ has the meaning indicated above)

Scheme 14

[a): In (III) Cl ₃ , ClCH ₂ CH ₂ Cl, reflux.

의 기이고, 여기서 # 및 R⁹가 각각 상기 나타낸 의미를 갖는 본 발명의 화학식 I-1의 화합물은 먼저 불활성 용매 중에서, 적절한 경우 산 및/또는 염기의 존재하에 하기 화학식 II의 인돌 유도체를 하기 화학식 III의 화합물 및 하기 화학식 IV의 말론산 에스테르와 축합시켜 하기 화학식 V의 화합물을 수득한 다음, 디에스테르를 탈카르복실화에 의해 분할시켜 하기 화학식 VI의 화합물을 수득한 다음, 후자를 불활성 용매 중에서 적합한 환원제, 예컨대 수소화리튬알루미늄을 이용하여 본 발명의 하기 화학식 I-1A의 화합물로 전환시킴으로써 제조될 수 있다.R ⁵ is a chemical formula

Wherein the compounds of the formula (I-1) of the present invention wherein # and R ⁹ each have the meanings indicated above are first prepared in an inert solvent, where appropriate indole derivatives of the formula (II) Condensation with a compound of formula III and a malonic acid ester of formula IV to give a compound of formula V, and then the diester is cleaved by decarboxylation to yield a compound of formula VI, the latter in an inert solvent It may be prepared by converting to a compound of formula I-1A of the present invention using a suitable reducing agent such as lithium aluminum hydride.

<Formula II>

Wherein R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above

<Formula III>

(Wherein R ⁹ has the meaning indicated above)

<Formula IV>

Wherein T ¹ and T ² are the same or different and are (C ₁ -C ₄ ) -alkyl or both together form a> C (CH ₃ ) ₂ bridge)

(V)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁹ , T ¹ and T ² have the meanings indicated above, respectively.

<Formula VI>

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above and T ³ is hydrogen or (C ₁ -C ₄ ) -alkyl)

<Formula I-1A>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above, respectively.

의 기이고, 여기서 # 및 R⁹가 각각 상기 나타낸 의미를 갖는 본 발명의 화학식 I-1의 화합물은 화학식 I-1A의 화합물로부터 출발하여 표준 방법에 의해 반응시켜 하기 화학식 VII의 화합물을 수득한 후, 알칼리 금속 시아나이드로 치환 반응시켜 본 발명의 하기 화학식 I-1B의 화합물을 수득함으로써 제조될 수 있다.R ⁵ is a chemical formula

Wherein compounds of formula (I-1) of the present invention wherein # and R ⁹ each have the meanings indicated above are reacted by standard methods starting from compounds of formula (I-1A) to obtain compounds of formula (VII) It can be prepared by the substitution reaction with an alkali metal cyanide to obtain a compound of formula (I-1B) of the present invention.

<Formula VII>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ each have the meaning indicated above and X is a suitable leaving group such as halogen, mesylate, tosylate or triflate

<Formula I-1B>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above, respectively.

Process step (II) + (III) + (IV)-> (V) can be carried out in one step as a three-component reaction, or first condensation of the aldehyde of formula III with malonic ester of formula IV by standard methods Can be carried out in two stages by reacting the latter with indole of formula II in a separate reaction step.

<Formula VIII>

(Wherein R ⁹ , T ¹ and T ² each have the meaning indicated above)

When the reaction (II) + (III) + (IV) → (V) is carried out in one step, the malonic ester component (IV) which is preferably used is a meldrum acid (cycl. Isopropylidene maloate). )to be. The product of formula Va obtained in this case is subsequently converted to ester [T ³ = methyl or ethyl] of formula VI by solubilization with methanol or ethanol in the presence of pyridine and copper powder (see [Y] Oikawa et al., Tetrahedron Lett., 1759-1762 (1978).

<Formula Va>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above, respectively.

One step process variant (II) + (III) + (IV) → (V), and when the reaction is carried out in two steps, condensation (III) + (IV) → (VIII) is preferably an acid / base catalyst For example in the presence of D, L-proline or piperidium acetate. The reaction (VIII) + (II)-> (V) can be advantageously carried out with the aid of an amine base such as triethylamine or Lewis acid such as copper (II) or ytterbium trifluoromethanesulfonate, where appropriate.

Suitable solvents for process steps (II) + (III) + (IV) → (V) and (VIII) + (II) → (V) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclo Hexanes, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene or bipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and acetonitrile There is this. It is likewise possible to use mixtures of the solvents mentioned. Acetonitrile is preferably used.

The reaction is generally carried out at temperatures in the range of 0 ° C to + 120 ° C, preferably 0 ° C to + 60 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (for example in the range of 0.5 to 5 bar). These are generally carried out under atmospheric pressure.

Suitable reducing agents for process step (VI) → (I-1A) are in particular lithium aluminum hydride or lithium borohydride. In the case of carboxylic acid (VI) [T ³ = H] it is also possible to alternatively use diborane or borane complexes. The reaction is preferably carried out at temperatures ranging from 0 ° C. to + 80 ° C. in ether, such as diethyl ether or tetrahydrofuran, as an inert solvent.

Particularly suitable inert solvents for process step (VII) → (I-1B) are ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, or bipolar aprotic Magnetic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and acetonitrile. It is likewise possible to use mixtures of these solvents. Dimethylformamide is preferably used. The reaction is generally carried out at temperatures in the range of + 20 ° C to + 150 ° C, preferably in the range of + 40 ° C to + 100 ° C.

Compounds of formulas (III) and (IV) may be commercially available, known from the literature, or prepared analogously to processes known in the literature.

The process described above is illustrated by the following synthetic scheme:

<Scheme 2>

(a): cat. D, L-proline, acetonitrile, RT; b): cat. Cu powder, EtOH / pyridine, reflux; c): LiAlH ₄ , Et ₂ O, 0 ° C. → RT; d): MsCl, Et ₃ N, DMAP, CH ₂ Cl ₂ , RT; e): KCN, DMF, 80 ° C.].

The indole of formula (II) is reacted with a 6-nitrobenzyl bromide derivative of formula (IX) with an alkali metal alkyl thiolate (X) in an inert solvent to give a compound of formula (XI), and the latter is then treated with vinyltomic bromide Bartoli) can be prepared by converting to indole of formula II.

<Formula IX>

(Wherein R ² , R ³ and R ⁴ each have the meaning indicated above)

<Formula X>

Wherein R ¹ has the meaning indicated above and Ak ⁺ is an alkali metal ion, preferably sodium

(XI)

Wherein R ¹ , R ² , R ³ and R ⁴ each have the meaning indicated above.

<Formula II>

Wherein R ¹ , R ² , R ³ and R ⁴ each have the meaning indicated above.

Suitable solvents for process steps (IX) + (X)-(XI) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclo Hexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene, or dipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and aceto Nitrile. It is likewise possible to use mixtures of the solvents mentioned. Tetrahydrofuran or DMF is preferably used.

The reaction is generally carried out at temperatures in the range of -20 ° C to + 100 ° C, preferably 0 ° C to + 60 ° C. The reaction can be carried out under atmospheric pressure, elevated pressure or reduced pressure (for example in the range of 0.5 to 5 bar). These are generally carried out under atmospheric pressure.

Suitable solvents for the Grignard reaction (XI)-(II) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclo Hexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene, or dipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and aceto Nitrile. It is likewise possible to use mixtures of the solvents mentioned. Tetrahydrofuran is preferably used.

The reaction is generally carried out at temperatures in the range of -100 ° C to + 50 ° C, preferably in the range of -78 ° C to + 25 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (for example in the range of 0.5 to 5 bar). These are generally carried out under atmospheric pressure.

Compounds of formula (IX) may be commercially available, known from the literature, or prepared analogously to processes known in the literature.

The process described above is illustrated by the following synthetic scheme:

<Scheme 3>

(a): NaSMe, THF, RT; b): vinylmagnesium bromide, -78 ° C].

Alternatively, indoles of Formula II wherein R ² , R ³ and R ⁴ are H can each be prepared as described exemplarily in the following synthetic scheme starting from 7-methylindole:

<Scheme 4>

(a): NaH, THF, 0 ° C. → RT; Di-tert-butyl dicarbonate, RT; b): N-bromosuccinimide, CCl ₄ , h.ν, reflux; c): NaSMe, DMF, RT; d): NaOMe, MeOH, RT].

의 기이고, 여기서 # 및 R⁹가 각각 상기 나타낸 의미를 갖는 추가의 본 발명의 화학식 I-1의 화합물은 화학식 I-1B의 화합물을 하기 화학식 XII의 화합물로 가수분해한 후, 불활성 용매 중에서 적합한 환원제, 예컨대 수소화리튬알루미늄과 반응시켜 본 발명의 하기 화학식 I-1C의 화합물을 수득함으로써 제조될 수 있다.R ⁵ is a chemical formula

Further compounds of formula (I-1) of the present invention, wherein # and R ⁹ each have the meanings indicated above are suitable in an inert solvent after hydrolysis of the compound of formula (I-1B) to a compound of formula (XII) It can be prepared by reacting with a reducing agent such as lithium aluminum hydride to obtain a compound of formula I-1C of the present invention.

<Formula XII>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above and T ⁴ is hydrogen or (C ₁ -C ₄ ) -alkyl)

<Formula I-1C>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above, respectively.

의 기이고, 여기서 # 및 R⁹가 각각 상기 나타낸 의미를 갖는 추가의 본 발명의 화학식 I-1의 화합물은 화학식 I-1C의 화합물을 표준 방법에 의해 한번 더 하기 화학식 XIII의 화합물과 반응시킨 후, 알칼리 금속 시아나이드와 치환 반응시켜 본 발명의 하기 화학식 I-1D의 화합물을 수득함으로써 제조될 수 있다.R ⁵ is a chemical formula

Wherein further compounds of formula (I-1) in which # and R ⁹ each have the meanings indicated above are reacted once more by a standard method with a compound of formula (XIII) It can be prepared by the substitution reaction with alkali metal cyanide to obtain a compound of formula (I-1D) of the present invention.

<Formula XIII>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ each have the meaning indicated above and X is a suitable leaving group such as halogen, mesylate, tosylate or triflate

<Formula I-1D>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meanings indicated above, respectively.

The hydrolysis of nitrile (I-1B) to carboxylic acid (XII) is preferably carried out in an aqueous solution of alkali or alkaline earth metal hydroxides such as lithium, sodium, potassium, calcium or barium hydroxide. Suitable cosolvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, other solvents such as Acetone, dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), or mixtures of these solvents. Hydrolysis is generally carried out at temperatures in the range of + 50 ° C to + 150 ° C, preferably in the range of + 60 ° C to + 100 ° C.

In the case of the synthesis sequence (I-1C) → (XII) → (I-1D), it is carried out under the reaction conditions for the sequence (I-1A) → (VII) → (I-1B).

The preparation of the compounds of the present invention can be illustrated by the following synthetic scheme:

Scheme 5

(a): aq. KOH, EtOH, 80 ° C .; b): LiAlH ₄ , THF, 60 ° C .; c): MsCl, Et ₃ N, DMAP, CH ₂ Cl ₂ , RT; d): KCN, DMF, 80 ° C.].

The process (II)-> (I-1A)-> (I-1B)-> (I-1C)-> (I-1D) described above is alternatively also represented by the formula I- Starting from the compound of formula II-2 or II-3 may be performed to prepare compounds such as 2A, I-3A, I-2B, I-3B, etc.

Scheme 15

(a): 2 equivalents of m-CPBA, CH ₂ Cl ₂ , 0 ° C. → RT; b): cat. D, L-proline, acetonitrile, RT; c): cat. Cu powder, EtOH / pyridine, reflux; d): LiAlH ₄ , Et ₂ O, 0 ° C. → RT; e): MsCl, Et ₃ N, DMAP, CH ₂ Cl ₂ , RT; f): KCN, DMF, 80 ° C.].

의 기이고, 여기서 # 및 R⁹가 각각 상기 나타낸 의미를 갖고, R¹⁰이 (C₄-C₆)-알킬이고, 여기서 (C₄-C₆)-알킬이 히드록시 및 시아노의 군으로부터 선택된 치환기로 치환되고, R¹¹이 수소인 추가의 본 발명의 화학식 I-1의 화합물은 화학식 I-1D의 화합물로부터 출발하여 공정 단계 (I-1B) → (XII) → (I-1C) → (XIII) → (I-1D)를 반복함으로써 제조될 수 있다.R ⁵ is a chemical formula

In which # and R ⁹ each have the meanings indicated above, and R ¹⁰ is (C ₄ -C ₆ ) -alkyl, wherein (C ₄ -C ₆ ) -alkyl is from the group of hydroxy and cyano A further compound of formula (I-1) of the invention, substituted with the selected substituents and R ¹¹ is hydrogen, starts from the compound of formula (I-1D), followed by process steps (I-1B) → (XII) → (I-1C) → It can be prepared by repeating (XIII) → (I-1D).

의 기이고, 여기서 # 및 R⁹가 각각 상기 나타낸 의미를 갖고, R¹⁰이 1-시아노-1-메틸에트-2-일, 1-시아노-2-메틸에트-2-일, 1-시아노-1,2-디메틸에트-2-일, 1-시아노-2,2-디메틸에트-2-일, 1-시아노-1-메틸프로프-3-일, 1-시아노-2-메틸프로프-3-일, 1-시아노-3-메틸프로프-3-일, 1-시아노-2,3-디메틸프로프-3-일, 1-히드록시-1-메틸에트-2-일, 1-히드록시-2-메틸에트-2-일, 1-히드록시-1,2-디메틸에트-2-일, 1-히드록시-2,2-디메틸에트-2-일, 1-히드록시-1-메틸프로프-3-일, 1-히드록시-2-메틸프로프-3-일, 1-히드록시-3-메틸프로프-3-일 또는 1-히드록시-2,3-디메틸프로프-3-일이고, R¹¹이 수소인 본 발명의 화학식 I의 화합물은 상기 기재된 화학식 VI 및 XII의 화합물로부터 출발하여 카르보닐 화합물의 α-메틸화 또는 α-디메틸화에 대해 당업자에게 공지된 방법에 의해 제조될 수 있다 [예를 들면, 반응식 6 참조].R ⁵ is a chemical formula

In which # and R ⁹ each have the meanings indicated above, and R ¹⁰ is 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1- Cyano-1,2-dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyano-1-methylprop-3-yl, 1-cyano- 2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxy-1-methyl Eth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1-hydroxy-2,2-dimethyleth-2- 1, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop-3-yl, 1-hydroxy-3-methylprop-3-yl or 1-hydroxy Compounds of the formula (I) of the invention wherein oxy-2,3-dimethylprop-3-yl and R ¹¹ is hydrogen are α-methylated or α-dimethyls of carbonyl compounds starting from the compounds of formulas VI and XII described above Can be prepared by methods known to those skilled in the art for the purposes of G., See Scheme 6.

<Scheme 6>

(a): di-tert-butyl dicarbonate, DMAP, THF, 50 ° C .; b): LDA, THF, -78 ° C; Then MeI, −78 ° C. → RT; c): TFA, CH ₂ Cl ₂ , RT; d): LiAlH ₄ , THF, 60 ° C .; e): MsCl, NEt ₃ , DMAP, CH ₂ Cl ₂ , RT; f): KCN, DMSO, 80 ° C .; g): 2 equivalents of meta-chloroperbenzoic acid, CH ₂ Cl ₂ , 0 ° C. → RT].

의 기이고, 여기서 # 및 R⁹가 각각 상기 나타낸 의미를 갖고, R¹⁰이 1-시아노에트-2-일, 1-시아노-1-메틸에트-2-일, 1-시아노-2-메틸에트-2-일, 1-시아노-1,2-디메틸에트-2-일, 1-시아노-2,2-디메틸에트-2-일, 1-시아노프로프-3-일, 1-시아노-1-메틸프로프-3-일, 1-시아노-2-메틸프로프-3-일, 1-시아노-3-메틸프로프-3-일, 1-시아노-2,3-디메틸프로프-3-일, 1-히드록시에트-2-일, 1-히드록시-1-메틸에트-2-일, 1-히드록시-2-메틸에트-2-일, 1-히드록시-1,2-디메틸에트-2-일, 1-히드록시-2,2-디메틸에트-2-일, 1-히드록시프로프-3-일, 1-히드록시-1-메틸프로프-3-일, 1-히드록시-2-메틸프로프-3-일, 1-히드록시-3-메틸프로프-3-일 또는 1-히드록시-2,3-디메틸프로프-3-일이고, 여기서 1-시아노에트-2-일, 1-시아노-1-메틸에트-2-일, 1-시아노-2-메틸에트-2-일, 1-시아노-1,2-디메틸에트-2-일, 1-시아노-2,2-디메틸에트-2-일, 1-시아노프로프-3-일, 1-시아노-1-메틸프로프-3-일, 1-시아노-2-메틸프로프-3-일, 1-시아노-3-메틸프로프-3-일, 1-시아노-2,3-디메틸프로프-3-일, 1-히드록시에트-2-일, 1-히드록시-1-메틸에트-2-일, 1-히드록시-2-메틸에트-2-일, 1-히드록시-1,2-디메틸에트-2-일, 1-히드록시-2,2-디메틸에트-2-일, 1-히드록시프로프-3-일, 1-히드록시-1-메틸프로프-3-일, 1-히드록시-2-메틸프로프-3-일, 1-히드록시-3-메틸프로프-3-일 및 1-히드록시-2,3-디메틸프로프-3-일이 1 또는 2개의 불소 치환기로 치환되고, R¹¹이 수소인 본 발명의 화학식 I의 화합물은 상기 기재된 화학식 VI, XII, I-1B 또는 I-1D의 화합물로부터 출발하여 카르보닐 화합물의 불소화에 대해 공지된 방법에 의해 제조될 수 있다 (예를 들면, 문헌 [Z. Xu et al., J. Fluorine Chem. 1992, 58(1), 71-79]; [W. H. Bunnelle, J. Org. Chem. 1990, 55, 768-770] 참조).R ⁵ is a chemical formula

Wherein # and R ⁹ each have the meanings indicated above, and R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2 -Methyleth-2-yl, 1-cyano-1,2-dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano- 2,3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1-hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1- Methylprop-3-yl, 1-hydroxy-2-methylprop-3-yl, 1-hydroxy-3-methylprop-3-yl or 1-hydroxy-2,3-dimethylprop -3-yl, wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano- 1,2-dimethyleth-2-yl, 1-cyano-2,2-dime Tileth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cyano-2-methylprop-3-yl, 1-sia No-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyeth-2-yl, 1-hydroxy-1-methyleth-2 -Yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1-hydroxy-2,2-dimethyleth-2-yl, 1 -Hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop-3-yl, 1-hydroxy-3-methylprop Compounds of the formula (I) of the invention wherein -3-yl and 1-hydroxy-2,3-dimethylprop-3-yl are substituted with one or two fluorine substituents and R ¹¹ is hydrogen, have the formula It can be prepared by known methods for the fluorination of carbonyl compounds starting from compounds of XII, I-1B or I-1D (see, eg, Z. Xu et al., J. Fluorine Chem. 1992). , 58 (1), 71-79; WH Bunnelle, J. Org. Chem. 1990, 55, 768-770).

의 기이고, 여기서 #, D, R⁶, R⁷, R⁸ 및 R⁹가 각각 상기 나타낸 의미를 갖고, R¹⁰이 (C₁-C₆)-알킬, (C₃-C₇)-시클로알킬 또는 페닐이고, 여기서 (C₃-C₇)-시클로알킬이 불소, 히드록시 및 시아노의 군으로부터 서로 독립적으로 선택된 1 또는 2개의 치환기로 치환될 수 있고, 여기서 페닐이 할로겐, 시아노, (C₁-C₄)-알킬, 트리플루오로메틸, (C₁-C₄)-알콕시, 트리플루오로메톡시 및 트리플루오로메틸티오의 군으로부터 서로 독립적으로 선택된 1 내지 3개의 치환기로 치환될 수 있고, R¹¹이 수소, 메틸, 에틸 또는 트리플루오로메틸인 본 발명의 화학식 I-1의 화합물은 불활성 용매 중에서 적합한 산 또는 루이스 산의 존재하에 화학식 II의 인돌을 하기 화학식 XI의 화합물과 반응시킴으로써 제조될 수 있다.R ⁵ is a chemical formula

In which #, D, R ⁶ , R ⁷ , R ⁸ and R ⁹ have the meanings indicated above, and R ¹⁰ is (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cyclo Alkyl or phenyl, wherein (C ₃ -C ₇ ) -cycloalkyl may be substituted with one or two substituents independently selected from the group of fluorine, hydroxy and cyano, wherein phenyl is halogen, cyano, To be substituted with 1 to 3 substituents independently selected from each other from the group of (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy and trifluoromethylthio And wherein R ¹¹ is hydrogen, methyl, ethyl or trifluoromethyl, reacting the indole of formula II with a compound of formula XI in the presence of a suitable acid or Lewis acid in an inert solvent Can be prepared by

(XI)

(Wherein R ⁵ has the meaning indicated above)

Process step (II) + (XI) → (I-1) is carried out in reaction step (II-2) + (XI) → (I-2) and (II-3) + (XI) → (I-3) Under the conditions mentioned.

The process described above is exemplarily illustrated by synthetic schemes 7 and 8:

Scheme 7

[a): Indium (III) chloride, toluene, 80 ° C.]

<Reaction Scheme 8>

[a): trifluoroacetic acid, CH ₂ Cl ₂ , RT]

의 기이고, 여기서 #, R⁹ 및 R¹¹이 각각 상기 나타낸 의미를 갖는 화학식 I의 화합물은 또한 당업자에게 공지된 방법에 의해 하기 화학식 XIV의 화합물을 하기 화학식 XV의 화합물과 반응시켜 하기 화학식 XVI의 화합물을 수득한 다음, 후자를 불활성 용매 중에서 루이스 산 또는 산의 존재하에 화학식 II, II-2 또는 II-3의 화합물과 반응시켜 하기 화학식 XVII, XVII-2 또는 XVII-3의 화합물을 수득한 다음, 후자를 불활성 용매 중에서 적합한 환원제에 의해 화학식 I-1A, I-2A 또는 I-3A로 환원시키거나, 또는 대안적으로 화학식 XVI의 화합물을 불활성 용매 중에서 적합한 환원제에 의해 하기 화학식 XVIII의 화합물로 환원시킨 다음, 후자를 상기 언급된 조건하에 화학식 II, II-2 또는 II-3의 화합물과 반응시켜 화학식 I-1A, I-2A 또는 I-3A의 화합물을 수득함으로써 제조될 수 있다.Alternatively, R ⁵ is of the formula

Wherein the compounds of formula (I) in which #, R ⁹ and R ¹¹ each have the meanings indicated above are also reacted with compounds of formula (XV) The compound was obtained, and then the latter was reacted with a compound of formula II, II-2 or II-3 in the presence of Lewis acid or acid in an inert solvent to obtain a compound of formula XVII, XVII-2 or XVII-3 , Reducing the latter to formula (I-1A, I-2A or I-3A) with a suitable reducing agent in an inert solvent, or alternatively reducing the compound of formula (XVI) to a compound of formula (XVIII) with a suitable reducing agent in an inert solvent The latter can then be prepared by reacting the latter with a compound of formula II, II-2 or II-3 under the conditions mentioned above to give a compound of formula I-1A, I-2A or I-3A. .

<Formula XIV>

(Wherein R ⁹ and R ¹¹ each have the meaning indicated above)

<Formula XV>

Wherein T ⁴ is (C ₁ -C ₄ ) -alkyl or benzyl)

<Formula XVI>

(Wherein R ⁹ , R ¹¹ and T ⁴ each have the meaning indicated above)

<Formula XVII>

<Formula XVII-2>

<Formula XVII-3>

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹¹ and T ⁴ each have the meaning indicated above.

<Formula XVIII>

(Wherein R ⁹ and R ¹¹ each have the meaning indicated above)

Suitable inert solvents for process steps (XVII) → (I-1A), (XVII-2) → (I-2A), (XVII-3) → (I-3A) and (XVI) → (XVIII) are in this case Alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or halohydrocarbons such as dichloromethane, trichloromethane, Tetrachloromethane or 1,2-dichloroethane, or other solvent such as dimethylformamide. It is likewise possible to use mixtures of the solvents mentioned. Tetrahydrofuran is preferably used.

Suitable reducing agents for process steps (XVII) → (I-1A), (XVII-2) → (I-2A), (XVII-3) → (I-3A) and (XVI) → (XVIII) borohydride Such as sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, aluminum hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or Diisobutylaluminum hydride or boron-tetrahydrofuran complex.

Reaction (IV-C) → (V-C) is generally carried out at a temperature of 0 ° C to + 60 ° C, preferably 0 ° C to + 40 ° C.

Compounds of formulas (XI), (XI-A), (XIV) and (XV) are either commercially available, known from the literature, or can be prepared analogously to processes known in the literature as exemplarily described by the following synthetic schemes. :

<Reaction Scheme 9>

[a): THF / Et ₂ O, 0 ° C. → RT].

<Reaction formula 10>

[a): THF / Et ₂ O, 0 ° C. → RT].

<Reaction Scheme 11>

(a): n-butyllithium (1.6N in hexane), THF, -78 ° C; Then p-chlorobenzaldehyde, -78 ° C → RT].

Scheme 16

(a): LiHMDS, THF, -78 ° C; Then ethyl acetate, -78 ° C; b): diisobutylaluminum hydride (1N in CH ₂ Cl ₂ ), THF, RT; c): indium (III) chloride, toluene, 80 ° C.].

Scheme 17

(a): vinylmagnesium bromide in THF, Et ₂ O, RT-reflux; b): MnO ₂ , CH ₂ Cl ₂ , reflux followed by H ₂ SO ₄ , K ₂ Cr ₂ O ₇ , 15-20 ° C .; c): trimethylsilyl 2,2-difluoro-2- (fluorosulfonyl) acetate, NaF, 110 ° C .; d): NaBH ₄ , EtOH, ethyl acetate, 40 ° C .; e): (CH ₃ CO) ₂ 0, pyridine, RT].

Scheme 18

(a): benzyltriethylammonium chloride, K ₂ CO ₃ , DMF, RT; b): sodium hydroxide solution, MeOH, RT; Hydrochloric acid; SOCl ₂ ; N, O-dimethylhydroxylamine hydrochloride, Et ₃ N, CH ₂ Cl ₂ , RT; c): chlorophenylmagnesium bromide in Et ₂ O, THF, RT-reflux; d): NaBH ₄ , EtOH, ethyl acetate, 40 ° C.].

Further, where appropriate, by conversion of the functional groups of the individual substitutions, especially those mentioned for A, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , starting from the compounds of formula (I) obtained by the process, Compounds of the invention can be prepared. These conversions are carried out by conventional methods known to those skilled in the art, for example nucleophilic, electrophilic or transition metal-catalyzed substitution reactions, oxidation, reduction, hydrogenation, alkylation, acylation, amination, esterification, Reactions such as ester cleavage, etherification, ether cleavage, the formation of carbonamides and sulfonamides, and the introduction and removal of transient protecting groups.

Compounds of the invention are selective for androgen (testosterone) and progesterone receptors and are distinguished by a range of pharmacological effects that could not be expected and distinguished by advantageous CYP inhibition profiles compared to the compounds disclosed in the prior art. It is a powerful antagonist. Thus, they are suitable for use as a medicament for the treatment and / or prevention of diseases in humans and animals.

The compounds of the present invention are characterized in the prevention and / or treatment of conditions associated with a variety of disorders and diseases, in particular elevated plasma aldosterone concentrations, or changes in plasma aldosterone concentrations relative to plasma renin concentrations or associated with such changes. Suitable. Examples that may be mentioned are: idiopathic primary hyperaldosteronemia, adrenal hyperplasia, hyperaldosteroneemia associated with adrenal adenoma and / or adrenal carcinoma, hyperaldosteronemia associated with cirrhosis, hyperaldosteronemia associated with heart failure, and essential hypertension (Relative) hyperaldosteronemia associated with.

The compounds of the present invention are also suitable for the prevention of sudden cardiac death in patients at high risk of sudden cardiac death due to their mechanism of action. These are, for example, patients with one of the following diseases: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, therapy-resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina , Myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathy such as Brugada syndrome, cardiomyopathy induced by Chagas disease, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and Ischemic attacks, strokes, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral blood flow disorders, arterial obstructions such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, hypertrophic deformation of the heart, pulmonary hypertension, coronary and peripheral artery spasms , Thrombosis, thromboembolic disorders, and vasculitis.

In addition, the compounds of the present invention include edema formation, such as pulmonary edema, kidney edema or heart failure-related edema, and recombination such as thrombolytic therapy, percutaneous coronary angioplasty (PTA) and coronary angioplasty (PTCA), heart It can be used for the prevention and / or treatment of restenosis after transplantation and bypass surgery.

In addition, the compounds of the present invention can be used for the prevention and / or treatment of erectile dysfunction.

In addition, the compounds of the present invention can be used as potassium-conservative diuretics, and in the form of gene-related forms such as electrolyte disturbances, such as hypercalcemia, hypernatremia or hypokalemia, such as Gitelman or Barrter syndrome. Suitable for

The compounds of the invention are likewise used in connection with organ transplantation for the treatment of kidney disorders such as acute and chronic renal failure, hypertensive kidney disease, atherosclerosis nephritis (chronic and interstitial), neurosis, chronic renal failure and cystic kidney disorders. It is suitable for the prevention of kidney damage, which may be caused by immunosuppressive agents such as cyclosporin A, and kidney cancer.

In addition, the compounds of the present invention can be used for the prevention and / or treatment of diabetes mellitus and diabetic sequelae such as neuropathy, nephropathy and cardiomyopathy.

In addition, the compounds of the present invention can be used for the prevention and / or treatment of ocular diseases, especially forms based on angiogenesis and neovascularization, such as neonatal retinopathy, diabetic retinopathy, and age-related macular degeneration and glaucoma. Can be used.

In addition, the compounds of the present invention can be used for the prophylaxis and / or treatment of microalbuminuria, and proteinuria, which can be caused, for example, by diabetes mellitus or hypertension.

The compounds of the present invention are also suitable for the prevention and / or treatment of diseases associated with an increase in suitable plasma glucocorticoid concentrations or a local increase in glucocorticoid concentrations in tissues (eg the heart). Examples that may be mentioned are: Adrenal dysfunction (Cushing syndrome), which causes overproduction of glucocorticoids, adrenal cortical tumors due to overproduction of glucocorticoids, and ACTH (adrenal cortical stimulating hormone) autonomously And pituitary tumors that produce adrenal hyperplasia that causes Cushing's disease.

In addition, the compounds of the present invention can be used for the prevention and / or treatment of obesity, metabolic syndrome and obstructive sleep apnea.

In addition, the compounds of the present invention may be used for, for example, inflammatory disorders caused by, for example, viruses, spirohetas, fungi, bacteria or mycobacteria, and unknown inflammatory disorders such as polyarthritis, lupus erythematosus, peripheral- or polyarteritis, skin It can be used for the prophylaxis and / or treatment of myositis, scleroderma and sarcoidosis.

In addition, the compounds of the present invention can be used for the treatment of neurological diseases such as depression, anxiety and chronic pain, in particular migraine, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's syndrome.

The compounds of the present invention may also be used for vascular injuries such as percutaneous transvascular coronary angioplasty (PTCA), stent grafts, postoperative vascular injuries such as coronary angiography, reclosure or restenosis after bypass surgery, and endothelial dysfunction, Raynaud) disease, obstructive thrombosis (Buerger syndrome) and tinnitus syndrome.

The compounds of the present invention are also suitable for the prophylaxis and / or treatment of gynecological disorders such as endometriosis, myoma, dysfunctional bleeding and dysmenorrhea.

The invention also relates to the use of the compounds of the invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

The invention also relates to the use of the compounds of the invention in the manufacture of a medicament for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

The invention also relates to methods for the treatment and / or prevention of disorders, in particular the disorders mentioned above, using an effective amount of one or more compounds of the invention.

The present invention also relates to the compounds of the present invention for use in methods for the treatment and / or prevention of aldosteroneism, hypertension, acute and chronic heart failure, sequelae of myocardial infarction, cirrhosis, renal failure and stroke.

The compounds of the present invention can be used alone or in combination with other active ingredients as necessary. The invention also relates to a medicament comprising at least one compound of the invention and at least one further active ingredient, in particular for the treatment and / or prophylaxis of the disorders mentioned above. Examples of suitable active ingredients for the combination are preferably as follows:

Active ingredients that lower blood pressure, such as preferably calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers and Rho kinase inhibitors;

Diuretics, in particular loop diuretics, and thiazide and thiazide-like diuretics;

Agents having an antithrombotic effect, for example preferably a group of platelet aggregation inhibitors, anticoagulants or profibrolytic substances;

Active ingredients that alter lipid metabolism, eg thyroid receptor agonists, cholesterol synthesis inhibitors, such as preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPARs Alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid absorbers, bile acid reuptake inhibitors and lipoproteins (a) antagonists;

Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidamine or SIN-1 and inhaled NO;

Compounds with a positive myotropy effect, such as cardiac glycosides (digoxin), beta-adrenergic and dopamine agonists such as isoproterenol, adrenaline, noradrenaline, dopamine and dobutamine;

Inhibitors of compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5 In particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil, and PDE 3 inhibitors such as amlinone and milnonone;

Natriuretic peptides such as atrial natriuretic peptide (ANP, anaride), type B natriuretic peptide or brain natriuretic peptide (BNP, necitride), type C natriuretic peptide (CNP) and urodilatin;

Calcium sensitizers, such as preferably lebocymendan;

NO- and heme-independent activators of guanylate cyclases, such as in particular sinasiguat and WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02 The compounds described in / 070510;

NO-independent heme-dependent stimulants of guanylate cyclases, such as the compounds described in particular for lyocigat and WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

Modulators of adenosine receptors, in particular adenosine A1 antagonists such as KW-3902, SLV-320 or BG-9928 (Adentri);

Vasopressin receptor antagonists such as connibaptan (Vaprisol), tolvaptan, satababtan, rixibabtan, reelcobtan, RWJ-339489 or RWJ-351647.

Inhibitors of human neutrophil elastase (HNE), such as ciberesstat or DX-890 (Leltran);

Compounds that inhibit signal transduction cascades, such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; And / or

Compounds affecting the energy metabolism of the heart, such as etomoxir, dichloroacetate, ranolazine or trimetazidine.

In a preferred embodiment of the invention, the compound of the invention is a diuretic, such as preferably furosemide, bumetanide, torsemide, bendroflumetiazide, chlorthiazide, hydrochlorthiazide, hydroflume Thiazide, methiclothiazide, polythiazide, triclomethiazide, chlortalidone, indamide, metolazone, quinetazone, acetazolamide, dichlorophenamide, metazolamide, glycerol, isosorbide, It is administered in combination with mannitol, amylolide or triamterene.

Agents that lower blood pressure preferably mean compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Rho kinase inhibitors, and diuretics. .

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with calcium antagonists such as nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with an angiotensin AII antagonist, such as preferably losartan, candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compound of the invention is an ACE inhibitor, such as preferably enalapril, captopril, ricinopril, ramipril, delapril, posinopril, quinopril, perindopril or trando It is administered in combination with a prill.

In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an endothelin antagonist, such as preferably bosentan, darthsentan, ambricentane or citaxentane.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as preferably aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with an alpha-1 receptor blocker, such as preferably prazosin.

In a preferred embodiment of the invention, the compound of the invention is a beta-receptor blocker, such as preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, fenbutolol, bufranolol, metipranolol , Nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, selifrolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, randiolol, nebivolol, It is administered in combination with epanolol or ad shindolol.

In a preferred embodiment of the invention, the compounds of the invention are Rho kinase inhibitors, such as preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA- In combination with 1049.

Agents with antithrombotic effect (antithrombotic agents) preferably mean compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrolytic substances.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with platelet aggregation inhibitors, such as preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with thrombin inhibitors, such as preferably xymellagatran, melagatran, vivalirudine or plexic acid.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a GPIIb / IIIa antagonist, such as preferably tyropiban or abeximab.

In a preferred embodiment of the invention, the compounds of the invention are factor Xa inhibitors, such as preferably ribaroxaban (BAY 59-7939), DU-176b, apixaban, otamicsaban, pydexaban, laxaxaban, Combination with Fondafariux, Hydrafariux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428 To be administered.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or low molecular weight (LMW) heparin derivatives.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a vitamin K antagonist, such as coumarin.

Agents that alter lipid metabolism are preferably CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or Compound from the group of PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid absorbers, bile acid reuptake inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor, such as preferably Dalcetrapib, BAY 60-5521, Anacetrapid or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compound of the invention is a thyroid receptor agonist, such as preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitrom (CGS 26214). In combination with).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with statin-based HMG-CoA reductase inhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin do.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis inhibitor, such as preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACAT inhibitor, such as preferably abashimib, melinamide, pastimib, eflusimib or SMP-797.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP inhibitor, such as preferably Implipidide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist, such as preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-delta agonist, such as preferably GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with cholesterol absorption inhibitors, such as ezetimibe, thyquaside or pharmaqueside.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipase inhibitor, such as orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid absorbent, such as preferably cholestyramine, cholestipol, cholesolbam, cholestagel or cholestimide.

In a preferred embodiment of the invention, the compounds of the invention are bile acid reuptake inhibitors, such as preferably ASBT (= IBAT) inhibitors, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or It is administered in combination with SC-635.

In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with lipoprotein (a) antagonists, such as gemcaben calcium (CI-1027) or nicotinic acid.

The invention also relates to a medicament comprising at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use thereof for the aforementioned purposes.

Compounds of the invention may have systemic and / or topical effects. To this end, it may be administered in a suitable manner, for example by oral, parenteral, lung, nasal, sublingual, tongue, buccal, rectal, skin, transdermal, conjunctival or ear routes, or as an implant or stent.

The compounds of the present invention may be administered in dosage forms suitable for these routes of administration.

Functions in accordance with the prior art to rapidly deliver and / or deliver the compound according to the invention in a modified manner and which contain the compound according to the invention in crystalline and / or amorphous and / or dissolved form, e.g. For example tablets (coated or coated tablets, such as gastrointestinal resistant coatings, or tablets with insoluble or delayed solubility and coatings which control the release of the compounds according to the invention), tablets which disintegrate rapidly in the oral cavity, or films / Wafers, films / lyophilizers, capsules (eg hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions are suitable for oral administration.

Parenteral administration includes, but is not limited to, absorption (eg, intravenous, intraarterial, intracardiac, spinal or lumbar) or by absorption (eg, intramuscular, subcutaneous, intradermal, transdermal, or peritoneal) Can be taken). Suitable dosage forms for parenteral administration are, in particular, preparations for injection and injection in the form of solutions, suspensions, emulsions, lyophilizers or sterile powders.

Suitable for other routes of administration include, for example, pharmaceutical forms for inhalation (particularly powder inhalers, nebulizers), nasal drops, solutions, sprays; Tablets, films / wafers or capsules, suppositories, preparations for ears and eyes, vaginal capsules, aqueous suspensions (lotion, shake mixtures), lipophilic suspensions, ointments, creams, transdermal treatment systems (eg Patches, milk, pastes, foams, dust powders, grafts or stents.

Oral or parenteral administration is preferred, and oral and intravenous administration is particularly preferred.

The compounds of the present invention can be converted to the dosage forms specified above. This can be done by mixing with inert, non-toxic, pharmaceutically suitable excipients in a known manner per se. These excipients include in particular carriers (eg microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (eg sodium dodecyl sulfate, polyoxy). Sorbitan oleate), binders (eg polyvinylpyrrolidone), synthetic and natural polymers (eg albumin), stabilizers (eg antioxidants such as ascorbic acid), colorants (eg Inorganic pigments such as iron oxide) and masking flavours and / or paints.

In general, it has proven advantageous to parenterally administer an amount of about 0.001 to 1 mg, preferably about 0.01 to 0.5 mg per kg of body weight to achieve an effective result. The dosage for oral administration is about 0.01 to 100 mg, preferably about 0.01 to 20 mg, very particularly preferably about 0.1 to 10 mg per kg of body weight.

Nevertheless, where appropriate, it may be necessary to deviate from the amounts specified above, particularly depending on body weight, route of administration, individual response to the active ingredient, type of formulation, and time or interval at which administration occurs. Thus, in some cases it may be sufficient to administer less than the minimum amount mentioned above, while in other cases the upper limit mentioned above must be exceeded. If relatively high doses are administered, it may be advisable to dispense them into several single doses throughout the day.

<Examples>

The following exemplary embodiments illustrate the invention. The invention is not limited by the following examples.

Unless indicated otherwise, percentage data in the following tests and examples are in weight percent and parts are parts by weight. Solvent ratios, dilution ratios, and concentration data of liquid / liquid solutions are in each case based on volume.

A. Example

Abbreviations and Acronyms:

Ac: Acetyl

aq .: aqueous, aqueous solution

Bn: Benzyl

Bu: Butyl

cat .: catalytic amount

CI: chemical ionization (MS)

conc .: concentrated

DAST: diethylaminosulfur trifluoride

dd: doublet of doublets (NMR)

ddd: doublet of doublet (NMR)

DMAP: 4-N, N-dimethylaminopyridine

DMF: Dimethylformamide

DMSO: Dimethyl Sulfoxide

EI: electron impact ionization (MS)

eq .: equivalent

ESI: Electrospray Ionization (MS)

Et: ethyl

EtOAc: ethyl acetate

h: hour

HPLC: high pressure, high performance liquid chromatography

LC-MS: coupled liquid chromatography-mass spectrometry

Me: methyl

min: min

Ms: methanesulfonyl (mesyl)

MS: mass spectrometry

NMR: nuclear magnetic resonance spectroscopy

Ph: Phenyl

RT: room temperature

Rt: retention time (HPLC)

SFC: Superfluid Chromatography

THF: tetrahydrofuran

UV: UV Spectroscopy

LC-MS and HPLC Methods:

Method 1 (HPLC):

Device: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / L water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 90% B → 9.2 min 2% B → 10 min 2% B; Flow rate: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.

Method 2 (HPLC):

Device: HP 1100 with DAD detection; Column: Chromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / L water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; Flow rate: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.

Method 3 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; Column: Phenomenex Synergi 2μ MAX-RP 100A mercury 20 mm × 4 mm; Eluent A: 1 L water + 0.5 ml 50% formic acid, eluent B: 1 L acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; Flow rate: 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.

Method 4 (LC-MS):

Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9μ 50 mm × 1 mm; Eluent A: 1 L water + 0.5 ml 50% formic acid, eluent B: 1 L acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; Flow rate: 0.33 ml / min; Oven: 50 ° C .; UV detection: 210 nm.

Method 5 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 series; UV DAD; Column: Phenomenex Gemini 3μ 30 mm × 3.00 mm; Eluent A: 1 L water + 0.5 ml 50% formic acid, eluent B: 1 L acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow rate: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.

Method 6 (LC-MS):

MS instrument type: Waters (Micromass) Quattro Micro; HPLC instrument type: Agilent 1100 Series; Column: Thermo Hypersil GOLD 3μ 20 mm × 4 mm; Eluent A: 1 L water + 0.5 ml 50% formic acid, eluent B: 1 L acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow rate 2.5 ml) → 5.0 min 100% A; Flow rate: 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.

Method 7 (GC-MS):

Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; Constant helium flow rate: 0.88 ml / min; Oven: 70 ° C .; Inlet: 250 ° C .; Gradient: 70 ° C., 30 ° C./min→310° C. (hold for 3 minutes).

Method 8 (LC-MS):

MS instrument type: Waters ZQ; HPLC instrument type: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3μ 20 mm × 4 mm; Eluent A: 1 L water + 0.5 ml 50% formic acid, eluent B: 1 L acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100% Flow rate: 2.5 ml / min, oven: 55 ° C .; Flow rate: 2 ml / ml; UV detection: 210 nm.

Method 9 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8μ 50 × 1 mm; Eluent A: 1 L water + 0.25 ml 99% formic acid, eluent B: 1 L acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A Oven: 50 ° C .; Flow rate: 0.40 ml / min; UV detection: 210-400 nm.

Starting Compounds and Intermediates:

Example 1A

2- (bromomethyl) -4-fluoro-1-nitrobenzene

574 g (3.70 mol) of 5-fluoro-2-nitrotoluene and 659 g (3.70 mol) of N-bromosuccinimide were introduced into 3.7 L of chloroform and 30.0 g (183 mmol) of 2,2 '-Azobis-2-methylpropanenitrile was added and the mixture was heated under reflux by heating with a UV lamp for 18 hours. After cooling, it was filtered by suction, the filtrate was concentrated, the residue was taken up in diethyl ether, filtered by suction and the filtrate was concentrated. The residue was dissolved in dichloromethane and petroleum ether and purified by flash chromatography (mobile phase: petroleum ether / ethyl acetate gradient) to yield 92.0 g (10% of theory) of the title compound.

Example 2A

1-fluoro-2-[(methylsulfanyl) methyl] -3-nitrobenzene

16.36 g (69.9 mmol) of 2-fluoro-6-nitrobenzyl bromide are introduced into 410 mL of THF, 5.88 g (83.9 mmol) of sodium methanethiolate are added in portions and the mixture is stirred at room temperature for 24 hours. It was. The solid was filtered off and the solvent was removed from the filtrate in a rotary evaporator. The residue was purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate 10/1) to afford 11.43 g (81% of theory) of the title compound.

Example 3A

1-[(ethylsulfanyl) methyl] -2-nitrobenzene

10.0 g (46.3 mmol) of 2-nitrobenzyl bromide were introduced into 100 mL of DMF at 0 ° C., 3.89 g (46.3 mmol) of sodium ethanethiolate were added in portions and the mixture was stirred at rt for 4 h. It was diluted with water, extracted with ethyl acetate and the organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate 9/1) to afford 7.40 g (81% of theory) of the title compound.

Example 4A

4-fluoro-2-[(methylsulfanyl) methyl] -1-nitrobenzene

10.0 g (42.7 mmol) of the compound from Example 1A were introduced into 100 mL of tetrahydrofuran at room temperature, 3.29 g (47.0 mmol) sodium methanethiolate was added and the mixture was stirred at room temperature for 4 hours. . It was filtered by suction through diatomaceous earth, washed with tetrahydrofuran and the filtrate was concentrated to give 9.00 g (100% of theory) of the title compound which was reacted without further purification.

Example 5A

1-tert-butoxycarbonyl-7-methyl-1H-indole

22.8 g (174 mmol) of 7-methyl-1H-indole were introduced under argon into 800 mL of anhydrous tetrahydrofuran at 0 ° C., and 7.30 g (183 mmol) of a 60% suspension of sodium hydride in mineral oil was added. The mixture was stirred at rt for 15 min. 39.8 g (183 mmol) of di-tert-butyl dicarbonate were added and the mixture was stirred at rt for 1 h. Then water was added and concentrated. The residue was taken up in water and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient) to yield 27.0 g (67% of theory) of the title compound.

Example 6A

7- (bromomethyl) -1-tert-butoxycarbonyl-1H-indole

200 mg (865 μmol) of the compound from Example 5A were introduced into 10 mL of tetrachloromethane, 169 mg (951 μmol) of N-bromosuccinimide were added, and the mixture was sunlit for 4 hours. Heated under reflux with irradiation. The residue was concentrated and then purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient) to yield 168 mg (63% of theory) of the title compound.

Example 7A

1-tert-butoxycarbonyl-7-[(methylsulfanyl) methyl] -1H-indole

160 mg (516 μmol) of the compound from Example 6A and 36.2 mg (516 μmol) sodium methanethiolate were stirred in 5 mL of dimethylformamide for 3 days at room temperature. Then water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient) to give 64 mg (45% of theory) of the title compound.

Example 8A

7-[(methylsulfanyl) methyl] -1H-indole

1.16 g (4.18 mmol) of the compound from Example 7A was introduced into 23 mL of methanol, 26 ml (113 mmol) of 25% methanolic sodium methanolate solution was added and the mixture was stirred at rt overnight. . Ice water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient) to yield 549 mg (74% of theory) of the title compound.

Example 9A

6-fluoro-7-[(methylsulfanyl) methyl] -1H-indole

A solution of 11.42 g (56.7 mmol) of the compound from Example 2A in 127 mL of tetrahydrofuran was slowly added dropwise to 284 ml (283.7 mmol) of a 0.7N solution of vinylmagnesium bromide in tetrahydrofuran at -78 ° C under argon. The solution was then stirred at -78 ° C for 2 hours. The reaction mixture was added to an ice cold saturated aqueous ammonium chloride solution, some ethyl acetate was added, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (mobile phase: cyclohexane / toluene / dichloromethane 10/10/1) to give 6.31 g (57% of theory) of the title compound.

Example 10A

7-[(ethylsulfanyl) methyl] -1H-indole

A solution of 7.40 g (37.5 mmol) of the compound from Example 3A in 195 mL tetrahydrofuran was added dropwise to 134 ml (93.8 mmol) of a 0.7N solution of vinylmagnesium bromide in tetrahydrofuran at -78 ° C under argon, The mixture was stirred at -78 ° C for 2 hours. The reaction mixture was then slowly added to an ice-cold saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate 9/1) to give 4.98 g (69% of theory) of the title compound.

Example 11A

5-fluoro-7-[(methylsulfanyl) methyl] -1 H-indole

180 ml (180 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran are added dropwise to a solution of 9.00 g (44.7 mmol) of the compound from Example 4A in 100 mL of tetrahydrofuran at −40 ° C. under argon and the mixture Was stirred at −40 ° C. for 3 hours. The reaction mixture was then added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: petroleum ether / ethyl acetate 9/1) to afford 5.00 g (57% of theory) of the title compound.

Example 12A

2,2-dimethyl-5-({7-[(methylsulfanyl) methyl] -1H-indol-3-yl} [4- (trifluoromethyl) phenyl] methyl) -1,3-dioxane- 4,6-dione

260 mg (12 mg of acetonitrile in 268 mg (1.54 mmol) of 4- (trifluoromethyl) benzaldehyde, 222 mg (1.54 mmol) of meldmic acid and 8.4 mg (0.07 mmol) of D, L-proline 1.47 mmol) is added to a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 504 mg (72% of theory) of the title compound.

Example 13A

5-[(4-chlorophenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane-4,6-dione

420 mg (2.40 mmol) of 20 mg of acetonitrile in 350 mg (2.49 mmol) of 4-chlorobenzaldehyde, 359 mg (2.49 mmol) of meldmic acid and 13.6 mg (0.12 mmol) of D, L-proline To a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 650 mg (62% of theory) of the title compound.

Example 14A

5-[(4-chlorophenyl) {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane-4,6-dione

1.00 g (7.14 mmol) of 4-chlorobenzaldehyde, 1.03 g (7.14 mmol) of meldmic acid and 39.1 mg (0.34 mmol) of D, L-proline in 1.30 g (6.80 mmol) in 57 mL of acetonitrile To a solution of the compound from Example 10A. The reaction mixture was stirred overnight at room temperature. It was concentrated, the crude product was stirred in diethyl ether, filtered and the precipitate was dried under high vacuum to give 1.38 g (44% of theory) of the title compound.

Example 15A

5-[(4-chloro-2-fluorophenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane- 4,6-dione

1.48 g (9.31 mmol) of 4-chloro-2-fluorobenzaldehyde, 1.34 g (9.31 mmol) of meldmic acid and 48.7 mg (0.42 mmol) of D, L-proline in 1.50 g (70 mL of acetonitrile) 8.46 mmol) is added to a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 3.60 g of the title compound were obtained, which were used without further purification.

Example 16A

5-[(4-chloro-2-fluorophenyl) {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1, 3-dioxane-4,6-dione

Purity 82% purity in 35 mL acetonitrile 0.70 g (4.41 mmol) 4-chloro-2-fluorobenzaldehyde, 0.64 g (4.41 mmol) meldmic acid and 24 mg (0.21 mmol) D, L-proline To a solution of 1.00 g (4.20 mmol) of the compound of Example 11A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.20 g of the title compound were obtained at 71% purity (78% of theory) and reacted without further purification.

Example 17A

5-[(2,4-dichlorophenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane-4,6 Dion

1.63 g (9.31 mmol) of 2,4-dichlorobenzaldehyde, 1.34 g (9.31 mmol) of meldmic acid and 48.7 mg (0.42 mmol) of D, L-proline in 1.50 g (8.46 mmol) in 70 mL of acetonitrile To a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 3.99 g (98% of theory) of the title compound were obtained, which were used without further purification.

Example 18A

5-[(2,4-dichlorophenyl) {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-di Oksan-4,6-dione

0.95 g (4.38 mmol) of 0.81 g (4.60 mmol) of 2,4-dichlorobenzaldehyde, 0.66 g (4.60 mmol) of meldmic acid and 25 mg (0.22 mmol) of D, L-proline in 36 mL of acetonitrile To a solution of the compound from Example 11A. The reaction mixture was stirred overnight at room temperature. It was concentrated to give 3.10 g (97% of theory) of the title compound in 68% purity, which was reacted without further purification.

Example 19A

5-[(4-chlorophenyl) {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane- 4,6-dione

1.00 g (4.20 mmol) in 34 mL of acetonitrile with 0.62 g (4.41 mmol) of 4-chlorobenzaldehyde, 0.64 g (4.41 mmol) of meldmic acid and 24 mg (0.21 mmol) of D, L-proline To a solution of the compound from Example 11A. The reaction mixture was stirred overnight at room temperature. It was concentrated to give 2.21 g (73% of theory) of the title compound in 64% purity, which was reacted without further purification.

Example 20A

2,2-dimethyl-5-[{7-[(methylsulfanyl) methyl] -1H-indol-3-yl} (naphthalen-2-yl) methyl] -1,3-dioxane-4,6- Dion

750 mg (4.23 mmol) of 694 mg (4.44 mmol) naphthalene-2-carbaldehyde, 640 mg (4.44 mmol) meldmic acid and 24 mg (0.21 mmol) of D, L-proline in 35 mL of acetonitrile ) Was added to a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. Then an additional 35 mL of acetonitrile was added and the mixture was stirred for 2 days at room temperature. It was concentrated and the residue was stirred in water and the precipitate was suction filtered and dried at 50 ° C. for 1 h under vacuum. The crude product was stirred in acetonitrile and the precipitate was suction filtered and dried under high vacuum to give 882 mg (45% of theory) of the title compound which was reacted without further purification.

Example 21A

5-[(4-chlorophenyl) {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane- 4,6-dione

1.44 g (10.24 mmol) of 4-chlorobenzaldehyde, 1.48 g (10.24 mmol) of meldmic acid and 0.06 g (0.51 mmol) of D, L-proline in 2.00 g (10.24 mmol) in 15 mL of acetonitrile To a solution of the compound from Example 9A. The reaction mixture was stirred overnight at room temperature. The precipitated solid was suction filtered, washed with acetonitrile and dried under high vacuum. 3.32 g (67% of theory) of the title compound were obtained.

Example 22A

2,2-dimethyl-5-({6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} [4- (trifluoromethyl) phenyl] methyl) -1, 3-dioxane-4,6-dione

The title compound was prepared analogously to the synthesis of the compound from Example 21A starting from 2.00 g (10.24 mmol) of compound from Example 9A and 1.78 g (10.24 mmol) of 4- (trifluoromethyl) benzaldehyde. 3.83 g (75% of theory) of the title compound were obtained.

Example 23A

5-[(1-benzothiophen-5-yl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane- 4,6-dione

1.02 g (5.66 mmol) of 1-benzothiophene-5-carbaldehyde, 0.82 g (5.66 mmol) of meldmic acid and 0.03 g (0.28 mmol) of D, L-proline are 1.00 in 8 mL of acetonitrile. g (5.66 mmol) was added to the solution of the compound from Example 8A. The reaction mixture was stirred at rt overnight, then the solvent was removed in vacuo. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 1.73 g (71% purity, 47% of theory) of the title compound.

Example 24A

5-[(2-bromo-1,3-thiazol-5-yl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1 , 3-dioxane-4,6-dione

1.02 g (7.08 mmol) of Meldrum's acid, 0.04 g (0.34 mmol) of D, L-proline and 1.36 g (7.08 mmol) of 2-bromo-5-formylthiazole are added in 1.30 g of acetonitrile. g (6.75 mmol) was added continuously to a solution of the compound from Example 8A. The reaction mixture was stirred at rt overnight, then the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (mobile phase: dichloromethane / methanol 95/5) to afford 3.58 g (81% purity, 87% of theory) of the title compound.

Example 25A

Ethyl 3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propanoate

0.7 mg (0.01 mmol) of copper powder was added to 504 mg (1.06 mmol) of the compound from Example 12A in 8 mL of pyridine and 2 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 241 mg (54% of theory) of the title compound.

Example 26A

tert-butyl 3- {3-ethoxy-3-oxo-1- [4- (trifluoromethyl) phenyl] propyl} -7-[(methylsulfanyl) methyl] -1 H-indole-1-carboxyl Rate

30 mL of 3.20 g (7.59 mmol) of the compound from Example 25A, 1.99 g (9.11 mmol) of di-tert-butyl dicarbonate and 0.09 g (0.76 mmol) of 4-N, N-dimethylaminopyridine It was dissolved in tetrahydrofuran and stirred at 50 ° C. for 2 hours. The reaction solution was mixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, the solid was filtered off and the solvent was removed in vacuo. 3.91 g (96% of theory) of the title compound were obtained.

Example 27A

tert-butyl 3- {3-ethoxy-2-methyl-3-oxo-1- [4- (trifluoromethyl) phenyl] propyl} -7-[(methylsulfanyl) methyl] -1 H-indole- 1-carboxylate

1.60 g (3.07 mmol) of the compound from Example 26A are dissolved in tetrahydrofuran at −78 ° C. and 3.2 ml (6.44 mmol) of a 2N solution of lithium diisopropylamide in tetrahydrofuran / n-heptane are slowly added dropwise. It was. After 5 minutes, 0.40 ml (6.44 mmol) iodomethane was added and the mixture was stirred at −78 ° C. for 2 hours and then warmed to room temperature over an additional 2 hours. The reaction solution was mixed with water, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, the solid was filtered off and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to afford 1.20 g (73% of theory) of the title compound as a mixture of diastereomers.

Example 28A

Ethyl 2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propanoate

2.52 g (4.71 mmol) of the compound from Example 27A were dissolved in 70 mL of dichloromethane and 14.5 ml (188.56 mmol) trifluoroacetic acid was added. After stirring at room temperature for 3 hours, the reaction solution is mixed with water, the phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, the solid was filtered off and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane / methanol 95/5) and preparative HPLC (mobile phase: acetonitrile-water gradient) to afford 1.01 g (48% of theory) of the title compound. Obtained as a mixture of stereoisomers.

Example 29A

Ethyl 3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

18 mg (0.28 mmol) of copper powder was added to 12.2 g (27.5 mmol) of the compound from Example 13A in 200 mL of pyridine and 55 mL of ethanol. The reaction mixture was heated at reflux for 4 hours. It was concentrated and the residue was taken up in dichloromethane and washed with water, 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient). 6.68 g (56% of theory) of the desired compound were obtained.

Example 30A

tert-butyl 3- [1- (4-chlorophenyl) -3-ethoxy-3-oxopropyl] -7-[(methylsulfanyl) methyl] -1H-indole-1-carboxylate

30 mL of 3.13 g (8.07 mmol) of the compound from Example 29A, 2.11 g (9.68 mmol) of di-tert-butyl dicarbonate and 0.10 g (0.81 mmol) of 4-N, N-dimethylaminopyridine It was dissolved in tetrahydrofuran and stirred at 50 ° C. for 2 hours. The reaction solution was mixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, the solid was filtered off and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 4.10 g (91% purity, 95% of theory) of the title compound.

Example 31A

tert-butyl 3- [1- (4-chlorophenyl) -3-ethoxy-2-methyl-3-oxopropyl] -7-[(methylsulfanyl) methyl] -1H-indole-1-carboxylate

The title compound was prepared analogously to the synthesis of the compound from Example 27A starting from 1.62 g (91% purity, 3.01 mmol) of the compound from Example 30A. 0.89 g (59% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 32A

Ethyl 3- (4-chlorophenyl) -2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

0.85 g (1.69 mmol) of the compound from Example 31A was dissolved in 10 mL of dichloromethane and 2.61 ml (33.86 mmol) of trifluoroacetic acid were added. After stirring for 2 hours at room temperature, the reaction solution is concentrated and the residue is purified twice by preparative HPLC (mobile phase: acetonitrile-water gradient). 0.42 g (61% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 33A

Ethyl 3- (4-chlorophenyl) -3- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} propanoate

2 mg (0.03 mmol) of copper powder was added to 1.38 g (3.00 mmol) of the compound from Example 14A in 15 mL of pyridine and 5 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulphate, filtered through silica gel and concentrated. 1.13 g of the desired compound were obtained at 84% purity (78% of theory).

Example 34A

Ethyl 3- (4-chloro-2-fluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

5.0 mg (0.08 mmol) of copper powder was added to 3.60 g (7.79 mmol) of the compound from Example 15A in 56 mL of pyridine and 14 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulphate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to afford 2.23 g (70% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column with chiral selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 10 μm, 250 mm × 30 mm; Eluent: isohexane / ethyl acetate 82:18; Flow rate: 45 ml / min; Temperature: RT; UV detection: 260 nm]. The separated enantiomer was purified again by preparative HPLC on achiral (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added):

Enantiomer 34A-1:

R _t = 4.37 min [column with chiral selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide), 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethyl acetate 4: 1; Flow rate: 1.5 ml / min; Temperature: RT; UV detection: 260 nm];

Enantiomer 34A-2:

R _t = 5.62 min [Column with Chiral Selector Poly (N-Methacryloyl-L-Leucine Dicyclopropylmethylamide), 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethyl acetate 4: 1; Flow rate: 1.5 ml / min; Temperature: RT; UV detection: 260 nm].

Example 35A

tert-butyl 3- [1- (4-chloro-2-fluorophenyl) -3-ethoxy-3-oxopropyl] -7-[(methylsulfanyl) methyl] -1H-indole-1-carboxyl Rate

5.00 g (12.3 mmol) of the compound from Example 34A were introduced into 50 mL of anhydrous tetrahydrofuran at 0 ° C. under argon, 0.52 g (12.9 mmol) of 60% suspension of sodium hydride in mineral oil was added and the mixture was Stir at room temperature for 15 minutes. 2.82 g (12.9 mmol) of di-tert-butyl dicarbonate were added and the mixture was stirred at rt overnight. Then water was added and the mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: toluene / ethyl acetate gradient) to give 6.1 g (98% of theory) of the title compound.

Example 36A

tert-butyl 3- [1- (4-chloro-2-fluorophenyl) -3-ethoxy-2-methyl-3-oxopropyl] -7-[(methylsulfanyl) methyl] -1 H-indole- 1-carboxylate

3.55 ml (7.10 mmol) of a 2N solution of lithium diisopropylamide in tetrahydrofuran were introduced into 40 mL of anhydrous tetrahydrofuran at −78 ° C. and 3.00 g (5.93 mmol) in 20 mL of tetrahydrofuran A solution of the compound from 35A was added and the mixture was stirred for 1 hour. 1.01 g (7.11 mmol) of methyl iodide was added at -78 ° C and the reaction mixture was allowed to warm to room temperature. It was then diluted with dichloromethane, the phases separated and the organic phase washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 2.45 g (80% of theory) of the title compound as a mixture of diastereomers. .

Example 37A

Ethyl 3- (4-chloro-2-fluorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

1.9 mg (0.03 mmol) of copper powder were added to the compound from Example 16A in 71% purity of 2.20 g (3.26 mmol) in 25 mL of pyridine and 6.7 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient) to yield 1.22 g (88% of theory) of the target compound.

Example 38A

Ethyl 3- (2,4-dichlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

5.3 mg (0.08 mmol) of copper powder were added to the compound from Example 17A of 3.99 g (8.34 mmol) in 59 mL of pyridine and 15 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulphate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 2.34 g (67% of theory) of the title compound.

Example 39A

Ethyl 3- (2,4-dichlorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

2.8 mg (0.05 mmol) of copper powder was added to the compound from Example 18A of 3.10 g (4.23 mmol) in 68% purity in 34 mL of pyridine and 8 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to give 1.52 g (82% of theory) of the title compound.

Example 40A

Ethyl 3- (4-chlorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

2.0 mg (0.03 mmol) of copper powder was added to the compound from Example 19A of 2.21 g (3.08 mmol) in 64% purity in 23 mL of pyridine and 6 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to give 1.29 g (82% of theory) of the title compound in 79% purity.

Example 41A

Ethyl 3- (4-chloro-2-methylphenyl) -3- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} propanoate

849 mg (5.49 mmol) of 4-chloro-2-methylbenzaldehyde, 791 mg (5.49 mmol) of meldmic acid and 30.1 mg (0.26 mmol) of D, L-proline in 1.00 g (5.23) of 44 mL of acetonitrile mmol) was added to the solution of the compound from Example 10A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in diethyl ether and the precipitate was separated and discarded. Concentration gave 2.70 g of crude product, of which 2.40 g was introduced into 9.5 mL of pyridine and 2.5 mL of ethanol and 0.9 mg (14 μmol) of copper powder were added. The reaction mixture was heated at reflux for 1 h. It was concentrated and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulphate, filtered through silica gel and concentrated. 950 mg of crude product were obtained, which were introduced into 14.2 mL of pyridine and 3.7 mL of ethanol and 1.3 mg (21 μmol) of copper powder were added. The reaction mixture was heated at reflux for 1 h. It was concentrated and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulphate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to afford 620 mg of the title compound.

Example 42A

Ethyl 3- (4-chloro-2-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

1.44 g (9.31 mmol) of 4-chloro-2-methylbenzaldehyde, 1.34 g (9.31 mmol) of meldmic acid and 48.7 mg (0.42 mmol) of D, L-proline in 1.50 g (8.46) in 70 mL of acetonitrile mmol) was added to the solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 3.43 g of crude product were obtained, which were introduced into 53 mL of pyridine and 14 mL of ethanol and 4.8 mg (75 μmol) of copper powder was added. The reaction mixture was heated at reflux for 1 h. It was concentrated and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulphate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 1.68 g (49% of theory) of the title compound.

Example 43A

Ethyl 3- (4-fluoro-2-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

750 mg (35 mg of acetonitrile) in 614 mg (4.44 mmol) of 4-fluoro-2-methylbenzaldehyde, 640 mg (4.44 mmol) of meldmic acid and 24.4 mg (0.21 mmol) of D, L-proline 4.23 mmol) is added to a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. An additional 35 mL of acetonitrile was added and the mixture was stirred at rt for 2 days. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added). 860 mg of product were obtained, which were introduced into 15 mL of pyridine and 5.2 mL of ethanol and 1.2 mg (19 μmol) of copper powder were added. The reaction mixture was heated at reflux for 2 hours. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 607 mg (37% of theory) of the title compound.

Example 44A

Ethyl 3- [2-fluoro-4- (trifluoromethyl) phenyl] -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

62 mL of aceto 1.54 g (8.00 mmol) of 2-fluoro-4- (trifluoromethyl) benzaldehyde, 1.15 g (8.00 mmol) of meldmic acid and 44 mg (0.38 mmol) of D, L-proline 1.50 g (7.62 mmol) in nitrile were added to a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated to give 4.47 g of crude product, which was introduced into 48 mL of pyridine and 12 mL of ethanol and 4 mg (63 μmol) of copper powder were added. The reaction mixture was heated at reflux for 1 h. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 2.74 g (82% of theory) of the title compound.

Example 45A

Ethyl 3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- (naphthalen-2-yl) propanoate

1.2 mg (0.02 mmol) of copper powder was added to 882 mg (1.92 mmol) of the compound from Example 20A in 15 mL of pyridine and 5 mL of ethanol. The reaction mixture was heated at reflux for 2 hours. It was concentrated and the crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) and preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to give 635 mg (82% of theory). The title compound was obtained.

Example 46A

Ethyl 4- (4-chlorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanoate

1.75 mL of concentrated sulfuric acid was added to 1.00 g (2.82 mmol) of the compound from Example 36 in 25 mL of ethanol. The reaction mixture was heated at reflux for 24 h. After cooling, the reaction mixture was added to saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, 0.1% formic acid added). 0.45 g (39% of theory) of the target compound were obtained.

Example 47A

Ethyl 3- (4-chlorophenyl) -3- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

23 mg (0.36 mmol) of copper powder were added to the compound from Example 21A of 3.31 g (7.16 mmol) in 13 mL of pyridine and 3 mL of ethanol. The reaction mixture was heated at reflux for 4 hours and then pyridine was removed in vacuo. The residue was taken up in ethyl acetate, silica gel was added and the mixture was concentrated. The crude product-silica gel mixture was first preliminarily purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate 5/1 to 3/1) and the product was again purified by preparative HPLC (acetonitrile / water gradient). 2.38 g (82% of theory) of the title compound were obtained.

Example 48A

Ethyl 3- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propanoate

The title compound was prepared analogously to the synthesis of the compound from Example 47A starting from 3.82 g (7.71 mmol) of the compound from Example 22A. 3.05 g (90% of theory) were obtained.

Example 49A

Ethyl 3- (1-benzothiophen-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

The title compound was prepared analogously to the synthesis of the compound from Example 47A starting from 1.73 g (71% purity, 3.72 mmol) of the compound from Example 23A. 1.23 g (81% of theory) of the title compound were obtained.

Example 50A

Ethyl 3- (2-bromo-1,3-thiazol-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

19 mg (0.29 mmol) of copper powder were added to 3.57 g (81% purity, 5.87 mmol) of the compound from Example 24A in 15 mL of pyridine and 8 mL of ethanol. The reaction mixture was heated at reflux for 5 hours and then copper was filtered through diatomaceous earth. The filtrate was concentrated, the residue was stirred with diethyl ether / dichloromethane and the precipitated solid was filtered off. The filtrate was concentrated and purified by preparative HPLC (acetonitrile / water gradient). 1.24 g (46% of theory) of the title compound were obtained.

Example 51A

3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propyl methanesulfonate

0.06 ml (0.45 mmol) triethylamine and 3.3 mg (0.03 mmol) 4-N, N-dimethylaminopyridine were added to 101 mg (0.27 mmol) of the compound from Example 1 in 5.5 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.03 ml (0.40 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 2 h, then diluted with dichloromethane, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, 0.1% formic acid added) afforded 101 mg (83% of theory) of the title compound.

Example 52A

3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

4.06 ml (29.1 mmol) triethylamine and 209 mg (1.71 mmol) 4-N, N-dimethylaminopyridine were added to 5.93 g (17.1 mmol) of the compound from Example 2 in 345 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 2.0 ml (25.7 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 2 h, then diluted with dichloromethane, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 6.90 g (95% of theory) of the title compound were obtained, which were reacted without further purification.

Example 53A

3- (4-chlorophenyl) -3- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.27 ml (1.96 mmol) triethylamine and 14.1 mg (0.12 mmol) 4-N, N-dimethylaminopyridine were added to 415 mg (1.15 mmol) of the compound from Example 3 in 23 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.13 ml (1.73 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 4 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, 0.1% formic acid added) afforded 520 mg (100% of theory) of the title compound.

Example 54A

3- (4-chloro-2-fluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

1.1 ml (7.77 mmol) triethylamine and 55.8 mg (0.46 mmol) 4-N, N-dimethylaminopyridine were added to 1.66 g (4.57 mmol) of the compound from Example 4 in 93 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.5 ml (6.85 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 4 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to afford 1.94 g (96% of theory) of the title compound.

Enantiomer 54A-1:

1.48 g (4.07 mmol) of enantiomer 4-1 were reacted analogously to the synthesis of the compound from Example 54A. 1.88 g (100% of theory) of the corresponding enantiomer of the title compound were obtained as crude product, which were reacted without purification.

Example 55A

3- (4-chloro-2-fluorophenyl) -2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.04 ml (0.27 mmol) triethylamine and 1.9 mg (0.02 mmol) 4-N, N-dimethylaminopyridine were added to 60 mg (0.16 mmol) of the compound from Example 5 in 4 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.02 ml (0.24 mmol) methanesulfonyl chloride was added. The reaction mixture was stirred at rt overnight, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 70 mg (97% of theory) of the title compound were obtained as a mixture of diastereomers which were reacted without further purification.

Example 56A

3- (4-chloro-2-fluorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.35 ml (2.54 mmol) triethylamine and 18.2 mg (0.15 mmol) 4-N, N-dimethylaminopyridine were added to 570 mg (1.49 mmol) of the compound from Example 6 in 40 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.17 ml (2.24 mmol) methanesulfonyl chloride was added. The reaction mixture was stirred at rt overnight, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 670 mg (98% of theory) of the title compound were obtained.

Example 57A

3- (2,4-dichlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

1.1 ml (7.93 mmol) triethylamine and 57.0 mg (0.47 mmol) 4-N, N-dimethylaminopyridine were added to 1.77 g (4.66 mmol) of the compound from Example 7 in 95 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.5 ml (7.00 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 4 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 1.98 g (93% of theory) of the title compound.

Example 58A

3- (2,4-dichlorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.6 ml (4.48 mmol) triethylamine and 32.2 mg (0.26 mmol) 4-N, N-dimethylaminopyridine were added to 1.05 g (2.64 mmol) of the compound from Example 8 in 53 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.3 ml (3.95 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 4 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 1.36 g (97% of theory) of the title compound were obtained, which were used without further purification.

Example 59A

3- (4-chlorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.3 ml (2.28 mmol) triethylamine and 16.4 mg (0.13 mmol) 4-N, N-dimethylaminopyridine were added to 488 mg (1.34 mmol) of the compound from Example 9 in 27 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.16 ml (2.01 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 4 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 445 mg (71% of theory) of the title compound were obtained, which were used without further purification.

Example 60A

3- (4-chloro-2-methylphenyl) -3- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

The title compound was prepared analogously to the synthesis of the compound from Example 54A starting from 250 mg (0.67 mmol) of the compound from Example 10. 308 mg (100% of theory) of the title compound were obtained.

Example 61A

3- (4-chloro-2-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

The title compound was prepared analogously to the synthesis of the compound from Example 54A starting from 1.24 g (3.46 mmol) of the compound from Example 11. 1.41 g (93% of theory) of the title compound were obtained.

Example 62A

3- (4-fluoro-2-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.17 ml (1.24 mmol) triethylamine and 8.9 mg (0.07 mmol) 4-N, N-dimethylaminopyridine were added to 250 mg (0.73 mmol) of the compound from Example 12 in 15 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.09 ml (1.09 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 2 h and then diluted with dichloromethane, washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 294 mg (96% of theory) of the title compound were obtained.

Example 63A

3- [2-fluoro-4- (trifluoromethyl) phenyl] -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

1.3 ml (9.41 mmol) triethylamine and 67.6 mg (0.55 mmol) 4-N, N-dimethylaminopyridine were added to 2.20 g (5.54 mmol) of the compound from Example 13 in 112 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.64 ml (8.30 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 4 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.66 g (94% of theory) of the title compound were obtained.

Example 64A

3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- (naphthalen-2-yl) propyl methanesulfonate

0.16 ml (1.18 mmol) triethylamine and 8.5 mg (0.07 mmol) 4-N, N-dimethylaminopyridine were added to 250 mg (0.69 mmol) of the compound from Example 14 in 15 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.08 ml (1.04 mmol) methanesulfonyl chloride were added. The reaction mixture was stirred at rt for 2 h and then diluted with dichloromethane, washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 302 mg (99% of theory) of the title compound were obtained.

Example 65A

4- (4-chlorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butyl methanesulfonate

0.14 ml (1.00 mmol) triethylamine and 7.2 mg (0.06 mmol) 4-N, N-dimethylaminopyridine were added to 212 mg (0.59 mmol) of the compound from Example 15 in 12 mL of dichloromethane. . The mixture was stirred at rt for 15 min, then 0.07 ml (0.88 mmol) methanesulfonyl chloride was added. The reaction mixture was stirred at rt for 2 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. 255 mg (98% of theory) of the title compound were obtained, which were reacted without further purification.

Example 66A

3- (4-chlorophenyl) -3- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.63 ml (4.53 mmol) triethylamine, 0.04 g (0.35 mmol) 4-N, N-dimethylaminopyridine and 0.3 ml (3.83 mmol) methanesulfonyl chloride were added 1.27 g (3.48) in 43 mL of dichloromethane. mmol) was added to the compound from Example 16. The reaction mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.55 g of the title compound were obtained as a crude product, which was reacted without further purification.

Example 67A

3- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propyl methanesulfonate

The title compound was prepared analogously to the synthesis of the compound from Example 66A starting from 1.81 g (4.55 mmol) of the compound from Example 17. 2.20 g of the title compound were obtained as crude product, which were reacted without further purification.

Example 68A

3- (1-benzothiophen-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

The title compound was prepared analogously to the synthesis of the compound from Example 66A starting from 640 mg (1.74 mmol) of the compound from Example 18. 768 mg of the title compound were obtained as a crude product, which was reacted without further purification.

Example 69A

3- (2-bromo-1,3-thiazol-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.25 ml (1.77 mmol) triethylamine, 15 mg (0.12 mmol) 4-N, N-dimethylaminopyridine and 0.1 ml (1.30 mmol) methanesulfonyl chloride 470 mg (1.18 mmol) in 20 ml dichloromethane To compound from Example 19). The reaction mixture was stirred at rt for 1 h, then diluted with dichloromethane, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 512 mg (91% of theory) of the title compound.

Example 70A

2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propyl methanesulfonate

The title compound was prepared analogously to the synthesis of the compound from Example 69A starting from 566 mg (1.44 mmol) of the compound from Example 20. 622 mg (92% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 71A

3- (4-chlorophenyl) -2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

The title compound was prepared analogously to the synthesis of the compound from Example 69A starting from 202 mg (0.56 mmol) of the compound from Example 21. 221 mg (90% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 72A

Ethyl 2-cyanocyclopropanecarboxylate [racemate trans-isomer]

40.2 g (291 mmol) of potassium carbonate were introduced into 89 mL of DMF at room temperature, 9.6 ml (146 mmol) of acrylonitrile, 15.5 ml (146 mmol) of ethyl chloroacetate and 1.96 g (8.61 mmol) of benzyl Triethylammonium chloride was added and the mixture was stirred at rt for 3 days. Water was added and the mixture was extracted with diethyl ether and the combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was purified by vacuum distillation. 6.50 g (30% of theory) of the title compound (boiling range: 63-66 ° C./0.9 mbar) and 1.41 g (7%) of the corresponding cis-isomer (boiling range: 85-89 ° C./0.9 mbar) are obtained It was.

Example 73A

2-cyano-N-methoxy-N-methylcyclopropanecarboxamide [racemate trans-isomer]

6.50 g (46.7 mmol) of the compound from Example 72A were introduced into 20 mL of methanol at room temperature, 46.7 ml (46.7 mmol) of 1N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 2 hours. Concentrated hydrochloric acid was then added until pH was 2, the mixture was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in 8.5 ml (117 mmol) thionyl chloride and stirred at 65 ° C. for 4 hours. After cooling it was concentrated and the residue was taken up twice in diethyl ether and again concentrated each time. The residue was introduced into 17 mL of dichloromethane, 3.43 g (35.1 mmol) of N, O-dimethylhydroxylamine hydrochloride and 9.8 ml (70.3 mmol) of triethylamine were added and the mixture was stirred at rt overnight. It was. Water was added, the phases were separated, extracted twice with dichloromethane, and the combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane / methanol 9/1) to afford 1.72 g (24% of theory) of the title compound.

Example 74A

2-[(4-chlorophenyl) carbonyl] cyclopropanecarbonitrile [racemate trans-isomer]

3.5 ml (3.50 mmol) of a 1N solution of chlorophenylmagnesium bromide in diethyl ether were introduced into 5 mL of THF under argon at room temperature and 490 mg (3.18 mmol) of compound from Example 73A in 5 mL of tetrahydrofuran. Solution was added and the mixture was heated at reflux for 2 h. Saturated aqueous ammonium chloride solution was added, extracted twice with diethyl ether, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. 714 mg of the title compound were obtained at 54% purity (59% of theory) and reacted without further purification.

Example 75A

2- [1- (4-chlorophenyl) -1-hydroxyethyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

714 mg (1.89 mmol) of 54% purity from Example 74A were introduced into 7 mL of diethyl ether at room temperature, 0.94 ml (2.83 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added, The mixture was stirred at rt overnight. The reaction mixture was added to an ice cold saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient) to give 257 mg (55% of theory) of the title compound.

Example 76A

1-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-ol

2.00 g (13.3 mmol) of 5-fluoro-1-indanon are introduced into 50 mL of diethyl ether at room temperature, 40 ml (20.0 mmol) of 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are added The mixture was stirred at rt overnight. The reaction mixture was added to an ice cold saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 2.22 g (87% of theory) of the title compound, which was reacted without further purification.

Example 77A

1-cyclopropyl-1- (4-fluorophenyl) ethanol

0.50 g (5.94 mmol) of acetylcyclopropane was dissolved in 5 mL of diethyl ether at 0 ° C. and 8.9 ml (8.91 mmol) of 1N solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran were slowly added dropwise. After stirring at 0 ° C. for 1 hour, warmed to room temperature, the reaction solution was mixed with water and ethyl acetate and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10/1) to yield 0.99 g (93% of theory) of the title compound.

Example 78A

1-cyclopropyl-1- (2,4-difluorophenyl) ethanol

1.50 g (9.61 mmol) of 2 ', 4'-difluoroacetophenone is dissolved in 8 mL of diethyl ether at 0 ° C. and 38.4 ml (19.21 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran Was slowly added dropwise. After stirring at 0 ° C. for 1 hour, warmed to room temperature, the reaction solution was mixed with water and ethyl acetate and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to yield 0.63 g (33% of theory) of the title compound.

Example 79A

1- (4-chloro-2-fluorophenyl) -1-cyclopropylethanol

114.6 ml (57.31 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran are dissolved in 23 mL of diethyl ether at 0 ° C. and 4.95 g (28.65 mmol) of 4'- dissolved in 5 mL of diethyl ether. Chloro-2'-fluoroacetophenone was slowly added dropwise. After stirring at 0 ° C. for 1 hour, warmed to room temperature, the reaction solution was mixed with acetonitrile, water and a small amount of diatomaceous earth, and the mixture was filtered through diatomaceous earth. The filtrate phases were separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and the solvent removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to give 4.30 g (70% of theory) of the title compound.

Example 80A

(4-fluorophenyl) [4- (trifluoromethyl) phenyl] methanol

1.00 g (5.71 mmol) of 4-bromofluorobenzene was dissolved in 10 mL of tetrahydrofuran at -78 ° C. 2.2 ml (6.86 mmol) of a 1.6N solution of n-butyllithium in hexane was added, followed by stirring for 15 minutes, followed by 1.26 g (6.86 mmol) trifluoro-p- dissolved in 10 mL of tetrahydrofuran. Tolualdehyde was added dropwise. The mixture was stirred at -78 ° C for 1 hour and then at room temperature for 1 hour. The reaction solution was mixed with water and dichloromethane and the phases were separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered and the solvent removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient). 1.02 g (66% of theory) of the title compound were obtained.

Example 81A

(4-chlorophenyl) (4-fluorophenyl) methanol

The title compound was prepared analogously to the synthesis of the compound from Example 80A starting from 6.00 g (34.29 mmol) 4-bromofluorobenzene and 5.78 g (41.14 mmol) 4-chlorobenzaldehyde. 7.14 g (88% of theory) of the title compound were obtained.

Example 82A

(4-fluoro-2-methylphenyl) (4-fluorophenyl) methanol

1.00 g (5.29 mmol) of 2-bromo-5-fluorotoluene was dissolved in 10 mL of tetrahydrofuran at -78 ° C. 4.0 ml (6.35 mmol) of a 1.6N solution of n-butyllithium in hexane were added, followed by stirring for 15 minutes, followed by 0.79 g (6.35 mmol) of p-fluorobenzaldehyde dissolved in 10 mL of tetrahydrofuran. Added dropwise. The mixture was warmed to rt and stirred for 1 h. The reaction solution was mixed with water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient). 0.56 g (43% of theory) of the title compound were obtained.

Example 83A

(4-chloro-2-methylphenyl) (4-fluorophenyl) methanol

The title compound was prepared analogously to the synthesis of the compound from Example 80A starting from 1.00 g (4.87 mmol) 2-bromo-5-chlorotoluene and 0.72 g (5.84 mmol) 4-fluorobenzaldehyde. 0.64 g (52% of theory) of the title compound were obtained.

Example 84A

(2,4-difluorophenyl) (4-fluorophenyl) methanol

The title compound was prepared analogously to the synthesis of the compound from Example 80A starting from 1.00 g (5.71 mmol) 4-bromofluorobenzene and 0.97 g (6.86 mmol) 2,4-difluorobenzaldehyde. 0.53 g (38% of theory) of the title compound were obtained.

Example 85A

(4-chloro-2-fluorophenyl) (4-fluorophenyl) methanol

The title compound was prepared analogously to the synthesis of the compound from Example 80A starting from 4.60 g (26.28 mmol) 4-bromofluorobenzene and 5.00 g (31.53 mmol) 4-chloro-2-fluorobenzaldehyde. . 4.45 g (66% of theory) of the title compound were obtained.

Example 86A

7-[(methylsulfonyl) methyl] -1H-indole

36.7 g (149 mmol) of 70% pure meta-chloroperbenzoic acid are added to 12.0 g (67.7 mmol) of the compound from Example 8A in 800 mL of tetrahydrofuran at 0 ° C. and the mixture is 15 minutes at room temperature. Was stirred. 100 mL of saturated aqueous sodium sulfite solution was added and then extracted several times with ethyl acetate. The combined organic phases were washed five times with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. 11.0 g (75% of theory) of the title compound were obtained.

Example 87A

5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

35.4 g (143 mmol) of 70% purity meta-chloroperbenzoic acid was added to the compound from Example 11A in 1 mL (700 mL of tetrahydrofuran) at 700C in 5 portions and the mixture was added Stir at room temperature for 30 minutes. The reaction mixture was added to saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted four times with dichloromethane, and the combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 15.7 g (84% of theory) of the title compound were obtained.

Example 88A

Ethyl 3-hydroxy-3- [4- (trifluoromethyl) phenyl] butanoate

19.9 ml (31.89 mmol) of a 1.6N solution of n-butyllithium in hexanes are added dropwise to a solution of 6.7 ml (31.89 mmol) of hexamethyldisilazane in 50 mL of tetrahydrofuran at 0 ° C. and the mixture for 15 minutes. After stirring, it was cooled to -78 ° C. 3.12 ml (31.89 mmol) ethyl acetate are added, the mixture is stirred for 1 hour, and 5.00 g (26.57 mmol) of 4-trifluoromethylacetophenone dissolved in 20 mL of tetrahydrofuran at -78 ° C. Stirred for 1 more hour. 1N hydrochloric acid was added to the reaction solution and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 8/2) to afford 7.14 g (97% of theory) of the title compound.

Example 89A

3- [4- (trifluoromethyl) phenyl] butane-1,3-diol

7.00 g (25.34 mmol) of the compound from Example 88A dissolved in 150 mL of tetrahydrofuran was added dropwise to 76.0 ml (76.0 mmol) of a 1N solution of diisobutylaluminum hydride in dichloromethane in 250 mL of tetrahydrofuran. The reaction mixture was stirred at rt for 3 h. After addition of 1N hydrochloric acid, the phases were separated, the aqueous phase was extracted with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution. Dry over sodium sulfate, filter and remove the solvent on a rotary evaporator. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane / methanol gradient) to give 5.55 g (91% purity, 85% of theory) of the title compound.

Example 90A

Ethyl 3- (4-chlorophenyl) -3-cyclopropyl-3-hydroxypropanoate

13.8 ml (22.14 mmol) of a 1.6N solution of n-butyllithium in hexanes are added dropwise to a solution of 4.7 ml (22.14 mmol) of hexamethyldisilazane in 17 mL of tetrahydrofuran at -20 ° C and the mixture is brought to 0 ° C. Stirred at 30 min, then cooled to -78 ° C again. 2.17 ml (22.14 mmol) ethyl acetate are added, the mixture is stirred for 30 minutes, and 2.00 g (11.07 mmol) 4-chlorophenyl cyclopropyl ketone dissolved in 17 mL of tetrahydrofuran is added,- It stirred at 78 degreeC for 1 hour. The reaction solution was mixed with 1N hydrochloric acid and ethyl acetate and the phases were separated. The organic phase was washed successively with 0.5N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient), acetonitrile was removed on a rotary evaporator and the aqueous phase was extracted several times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. 2.54 g (99% of theory) of the title compound were obtained.

Example 91A

Ethyl 3- (2,3-dihydro-1,4-benzodioxin-6-yl) -3-hydroxybutanoate

The title compound was prepared analogously to the synthesis of the compound from Example 90A starting from 2.00 g (11.22 mmol) of 1,4-benzodioxan-6-yl methyl ketone and 4.74 ml (22.45 mmol) ethyl acetate. 2.52 g (84% of theory) of the title compound were obtained.

Example 92A

5-[(4-chloro-2-methylphenyl) {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3- Dioxane-4,6-dione

0.68 g (4.41 mmol) of 4-chloro-2-methylbenzaldehyde, 0.64 g (4.41 mmol) of meldmic acid and 24.0 mg (0.21 mmol) of D, L-proline are 1.00 g (4.20) in 35 mL of acetonitrile. mmol) was added to a solution of the compound from Example 11A in 82% purity. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.40 g of the title compound were obtained, which were used without further purification.

Example 93A

5-([2-chloro-4- (trifluoromethyl) phenyl] {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl) -2,2-dimethyl-1,3 Dioxane-4,6-dione

57 mL of acetonitrile with 1.50 g (7.19 mmol) of 2-chloro-4- (trifluoromethyl) benzaldehyde, 1.04 g (7.19 mmol) of melt acid and 39.4 mg (0.34 mmol) of D, L-proline 1.21 g (6.85 mmol) in a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in diethyl ether and concentrated again. 3.64 g (75% of theory, 72% pure) of the title compound were obtained, which were used without further purification.

Example 94A

2,2-dimethyl-5-[(4-methylphenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -1,3-dioxane-4,6-dione

1.28 g (10.7 mmol) of 4-methylbenzaldehyde, 1.54 g (10.7 mmol) of meldmic acid and 58.0 mg (0.51 mmol) of D, L-proline in 2.00 g (10.2 mmol) in 80 mL of acetonitrile To a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. It was concentrated and the residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 4.34 g of the title compound were obtained, which were used without further purification.

Example 95A

5-[(4-chloro-3-fluorophenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3-dioxane- 4,6-dione

1.34 g (8.46 mmol) of 4-chloro-3-fluorobenzaldehyde, 1.22 g (8.46 mmol) of meldmic acid and 0.05 g (0.42 mmol) of D, L-proline in 1.50 g (12 mL of acetonitrile) 8.46 mmol) is added to a solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. The precipitated solid was suction filtered, washed with acetonitrile and dried under high vacuum. 2.42 g (98% of theory) of the title compound were obtained.

Example 96A

5-[(4-chloro-2,6-difluorophenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2-dimethyl-1,3- Dioxane-4,6-dione

1.64 g (9.31 mmol) of 4-chloro-2,4-difluorobenzaldehyde, 1.22 g (8.46 mmol) of meldmic acid and 0.05 g (0.42 mmol) of D, L-proline in 12 mL of acetonitrile 1.50 g (8.46 mmol) was added to the solution of the compound from Example 8A. The reaction mixture was stirred overnight at room temperature. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 1.61 g (36% of theory) of the title compound.

Example 97A

5-[(2,2-difluoro-1,3-benzodioxol-5-yl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] -2,2 -Dimethyl-1,3-dioxane-4,6-dione

1.57 g (8.46 mmol) of 2,2-difluoro-1,3-benzodioxol-5-carbaldehyde, 1.22 g (8.46 mmol) of melt acid and 0.05 g (0.42 mmol) of D, L Proline was added to a solution of the compound from Example 8A of 1.50 g (8.46 mmol) in 12 mL of acetonitrile. The reaction mixture was stirred overnight at room temperature. The precipitated solid was suction filtered, washed with acetonitrile and dried under high vacuum. 2.67 g (91% of theory) of the title compound were obtained.

Example 98A

Ethyl 3- (4-chloro-2-methylphenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

2.1 mg (34 μmol) of copper powder was added to a solution of 2.48 g of compound from Example 92A in 28 mL of pyridine and 8 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient) to yield 0.69 g of the title compound.

Example 99A

Ethyl 3- [2-chloro-4- (trifluoromethyl) phenyl] -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

2.8 mg (45 μmol) of copper powder was added to a solution of the compound from Example 93A of 3.64 g (approximately 5.12 mmol, 72% purity) in 41 mL of pyridine and 10 mL of ethanol. The reaction mixture was heated at reflux overnight. It was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to give 1.34 g (57% of theory) of the title compound.

Example 100A

Ethyl 3- (4-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

6.5 mg (102 μmol) of copper powder were added to a solution of 4.34 g of the compound from Example 94A in 75 mL of pyridine and 20 mL of ethanol. The reaction mixture was heated at reflux for 1 h. It was concentrated and the crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to afford 2.55 g of the title compound.

Example 101A

Ethyl 3- (4-chloro-3-fluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

17 mg (262 μmol) of copper powder was added to a solution of 2.42 g (5.24 mmol) of the compound from Example 95A in 10 mL of pyridine and 2 mL of ethanol. The reaction mixture was heated at reflux for 4 hours. It was concentrated and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 1.82 g (85% of theory) of the title compound.

Example 102A

Ethyl 3- (4-chloro-2,6-difluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

11 mg (166 μmol) of copper powder were added to a solution of 1.60 g (3.33 mmol) of compound from Example 96A in 6 mL of pyridine and 1.3 mL of ethanol. The reaction mixture was heated at reflux for 4 hours. It was concentrated and the crude product was first purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5/1) followed by preparative HPLC (mobile phase: acetonitrile / water gradient). 1.15 g (81% of theory) of the title compound were obtained.

Example 103A

Ethyl 3- (2,2-difluoro-1,3-benzodioxol-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

17 mg (271 μmol) of copper powder was added to a solution of the compound from Example 97A of 2.66 g (5.43 mmol) in 10 mL of pyridine and 2 mL of ethanol. The reaction mixture was heated at reflux for 4 hours. It was concentrated and the crude product was first purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient) followed by preparative HPLC (mobile phase: acetonitrile / water gradient). 1.73 g (74% of theory) of the title compound were obtained.

Example 104A

Ethyl 3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanoate

3.42 g (14.10 mmol) ethyl 3- (4-chlorophenyl) -3-hydroxybutanoate (prepared similar to the synthesis of Example 88A starting from 4-chloroacetophenone and ethyl acetate) and 3.12 g ( 14.10 mmol) of indium (III) chloride was added to 2.50 g (14.10 mmol) of the compound from Example 8A in 100 mL of toluene. The reaction mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, the reaction solution was mixed with water and ethyl acetate and the solids were filtered off. The phases of the filtrate were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane / methanol 95/5) followed by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 0.98 g (17% of theory) of the title compound. Obtained.

Example 105A

Ethyl 3- (4-chlorophenyl) -3-cyclopropyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propanoate

700 mg (2.61 mmol) of the compound from Example 90A and 576 mg (2.61 mmol) of indium (III) chloride were added to 462 mg (2.61 mmol) of the compound from Example 8A in 11 mL of toluene. The reaction mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, the solid was filtered through silica gel and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 69 mg (6% of theory) of the title compound.

Example 106A

Ethyl 3- (2,3-dihydro-1,4-benzodioxin-6-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanoate

600 mg (2.25 mmol) of the compound from Example 91A and 0.21 ml (2.70 mmol) of trifluoroacetic acid were added to 399 mg (2.25 mmol) of the compound from Example 8A in 4 mL of dichloromethane. The reaction mixture was stirred at rt for 30 min. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 576 mg (60% of theory) of the title compound.

Example 107A

3- (4-chloro-2-methylphenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

512 mg (1.36 mmol) of the compound from Example 132 in 25 mL of dichloromethane were mixed with 0.32 ml (2.30 mmol) triethylamine and 16.6 mg (0.13 mmol) 4-N, N-dimethylaminopyridine And stirred at room temperature for 15 minutes. 0.16 ml (2.03 mmol) methanesulfonyl chloride was then added and the mixture was stirred at rt for 4 h. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 608 mg (98% of theory) of the title compound were obtained, which were further reacted directly without further purification.

Example 108A

3- [2-chloro-4- (trifluoromethyl) phenyl] -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

560 mg (1.35 mmol) of the compound from Example 133 in 22 mL of dichloromethane were mixed with 0.32 ml (2.30 mmol) triethylamine and 16.5 mg (0.14 mmol) 4-N, N-dimethylaminopyridine And stirred at room temperature for 15 minutes. 0.16 ml (2.03 mmol) methanesulfonyl chloride was then added and the mixture was stirred at rt for 4 h. It was diluted with dichloromethane and washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 664 mg (100% of theory) of the title compound were obtained, which were reacted further directly without further purification.

Example 109A

3- (4-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

1.77 g (5.44 mmol) of the compound from Example 134 in 100 mL of dichloromethane were mixed with 1.3 ml (9.25 mmol) of triethylamine and 66.4 mg (0.54 mmol) of 4-N, N-dimethylaminopyridine And stirred at room temperature for 15 minutes. Then 0.63 ml (8.16 mmol) methanesulfonyl chloride were added and the mixture was stirred at rt for 4 h. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.08 g (95% of theory) of the title compound were obtained, which were reacted directly further without further purification.

Example 110A

3- (4-chloro-3-fluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.52 ml (3.70 mmol) triethylamine, 0.04 g (0.28 mmol) 4-N, N-dimethylaminopyridine and 0.24 ml (3.13 mmol) methanesulfonyl chloride were 1.03 g (2.84) in 35 mL dichloromethane. mmol) was added to the compound from Example 135. The reaction mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.30 g of the title compound were obtained as crude product, which was reacted without further purification.

Example 111A

3- (4-chloro-2,6-difluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.40 ml (2.89 mmol) triethylamine, 0.03 g (0.22 mmol) 4-N, N-dimethylaminopyridine and 0.194 ml (2.45 mmol) methanesulfonyl chloride 0.85 g (2.23 in 28 mL dichloromethane) mmol) was added to the compound from Example 136. The reaction mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.05 g of the title compound were obtained as crude product, which was reacted without further purification.

Example 112A

3- (2,2-difluoro-1,3-benzodioxol-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.49 ml (3.52 mmol) triethylamine, 0.03 g (0.27 mmol) 4-N, N-dimethylaminopyridine and 0.23 ml (2.98 mmol) methanesulfonyl chloride were added 1.06 g (2.71) in 33 mL dichloromethane. mmol) was added to the compound from Example 137. The reaction mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 1.35 g of the title compound were obtained as a crude product, which was reacted without further purification.

Example 113A

3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] butyl methanesulfonate

135 mg (0.34) in 10 mL dichloromethane with 0.07 ml (0.52 mmol) triethylamine, 4 mg (0.03 mmol) 4-N, N-dimethylaminopyridine and 0.03 ml (0.38 mmol) methanesulfonyl chloride mmol) was added to the compound from Example 138. The reaction mixture was stirred at rt for 1 h, water was added and the solvent removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 118 mg (73% of theory) of the title compound.

Example 114A

3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butyl methanesulfonate

0.23 ml (1.65 mmol) triethylamine, 13 mg (0.11 mmol) 4-N, N-dimethylaminopyridine and 0.09 ml (1.21 mmol) methanesulfonyl chloride in 395 mg (1.10) in 30 mL dichloromethane mmol) was added to the compound from Example 139. The reaction mixture was stirred at rt for 1 h, water was added and the solvent removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 439 mg (73% of theory) of the title compound.

Example 115A

3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} pentyl methanesulfonate

0.39 ml (2.81 mmol) triethylamine, 23 mg (0.23 mmol) 4-N, N-dimethylaminopyridine and 0.16 ml (2.06 mmol) methanesulfonyl chloride in 50 mL dichloromethane (1.10 mmol) was added to the compound from Example 140. The reaction mixture was stirred at rt for 1 h, water was added and the solvent removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 782 mg (92% of theory) of the title compound.

Example 116A

3- (4-chlorophenyl) -3-cyclopropyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propyl methanesulfonate

0.02 ml (0.02 mmol) triethylamine, 2 mg (0.01 mmol) 4-N, N-dimethylaminopyridine and 0.01 ml (0.14 mmol) methanesulfonyl chloride 47 mg (0.12) in 1.5 mL dichloromethane mmol) was added to the compound from Example 141. The reaction mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 57 mg of the title compound were obtained as crude product, which were reacted without further purification.

Example 117A

3- (2,3-dihydro-1,4-benzodioxin-6-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butyl methanesulfonate

443 mg (1.15) in 14 mL of dichloromethane with 0.21 ml (1.50 mmol) triethylamine, 14 mg (0.12 mmol) 4-N, N-dimethylaminopyridine and 0.10 ml (1.27 mmol) methanesulfonyl chloride mmol) was added to the compound from Example 142. The reaction mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 532 mg of the title compound were obtained as crude product, which were reacted without further purification.

Example 118A

5-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-ol

45 ml (22.5 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were diluted with 5-chloro-2,3-dihydro-1H-inden-1-one and 6-chloro in 56 mL of diethyl ether at room temperature. To 2.50 g (15.0 mmol) of a mixture of -2,3-dihydro-1H-inden-1-one, the mixture was stirred at rt overnight. The reaction mixture is added to ice water, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) and preparative HPLC (mobile phase: acetonitrile / water gradient) to give 71.0 mg (2% of theory) of 5-chloro-1- A mixture of cyclopropyl-2,3-dihydro-1H-inden-1-ol and 6-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-ol was obtained.

Example 119A

6-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-ol

45 ml (22.5 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were diluted with 5-chloro-2,3-dihydro-1H-inden-1-one and 6-chloro in 56 mL of diethyl ether at room temperature. To 2.50 g (15.0 mmol) of a mixture of -2,3-dihydro-1H-inden-1-one, the mixture was stirred at rt overnight. The reaction mixture is added to ice water, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) and preparative HPLC (mobile phase: acetonitrile / water gradient) to give 152 mg (5% of theory) of the title compound.

Example 120A

2,2-difluoro-N-methoxy-N-methylcyclopropanecarboxamide

6.32 g (64.8 mmol) of 7.00 g (49.8 mmol) of 2,2-difluorocyclopropanecarbonyl chloride (described in Journal of Fluorine Chemistry 1990, 49, 127-139) in 100 mL of dichloromethane. ) Was mixed with N, O-dimethylhydroxylamine hydrochloride and 18.1 ml (130 mmol) triethylamine and stirred overnight at room temperature. Water was added to the reaction mixture, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated. 5.73 g (70% of theory) of the title compound were obtained, which were used without further purification.

Example 121A

2-Chloro-N-methoxy-N, 4-dimethylbenzamide

1.25 g (6.61 mmol) of 2-chloro-4-methylbenzoyl chloride in 4 mL of dichloromethane are 0.84 g (8.60 mmol) of N, O-dimethylhydroxylamine hydrochloride and 2.4 ml (17.2 mmol) of triethyl Mix with amine and stir for 24 hours. Water and 1N hydrochloric acid were added to the reaction mixture, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to afford 1.10 g (78% of theory) of the title compound.

Example 122A

2- [4- (trifluoromethyl) benzoyl] cyclopropanecarbonitrile [racemate trans-isomer]

Under argon, a solution of 4.00 g (14.7 mmol) of 1-iodo-4- (trifluoromethyl) benzene in a few drops of dibromoethane and 10 mL of dry diethyl ether was added to 40 mL of dry diethyl. To 375 mg (15.4 mmol) of magnesium in ether was added and the mixture was heated at reflux for 2 hours. After cooling, the reaction supernatant was added dropwise to 2.00 g (13.0 mmol) of the compound from Example 73A in 50 mL of THF under argon, and the mixture was stirred at rt overnight. The reaction solution was then added to saturated aqueous ammonium chloride solution, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 1.42 g (46% of theory) of the title compound.

Example 123A

2- (2,4-difluorobenzoyl) cyclopropanecarbonitrile [racemate trans-isomer]

Under argon, 661 mg (27.2) of 5.00 g (25.9 mmol) of 2,4-difluorobromobenzene dissolved in a few drops of dibromoethane followed by 50 mL of diethyl ether. mmol). The mixture was heated at reflux for 2 hours. After cooling, the reaction supernatant was added dropwise to a solution of 3.63 g (23.5 mmol) of the compound from Example 73A in 80 mL of THF under argon, and the mixture was stirred at rt overnight. The reaction solution was then added to saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 2.15 g (44% of theory) of the title compound.

Example 124A

(4-chlorophenyl) (2,2-difluorocyclopropyl) methanone

A solution of 2.00 g (12.1 mmol) of the compound from Example 120A in 20 mL of THF is added to 2.87 g (13.3 mmol) of a 1N chlorophenylmagnesium bromide solution in diethyl ether in 20 mL of THF under argon at room temperature, The mixture was heated at reflux for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution, extracted twice with diethyl ether, and the combined organic phases were dried over magnesium sulfate and concentrated. 2.47 g (94% of theory) of the title compound were obtained, which were used without further purification.

Example 125A

(2-Chloro-4-methylphenyl) (cyclopropyl) methanone

7.7 ml (7.65 mmol) of 1N cyclopropylmagnesium bromide solution in THF were added to 1.09 g (5.10 mmol) of the compound from Example 121A in 19 mL of diethyl ether and the mixture was stirred at rt overnight. 7.7 ml (7.65 mmol) of 1N cyclopropylmagnesium bromide solution in additional THF were added and the mixture was stirred at rt overnight. The reaction mixture is added to ice water, extracted with dichloromethane, the organic phase is dried over magnesium sulphate, filtered and concentrated and the crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) , 326 mg (33% of theory) of the title compound were obtained.

Example 126A

2- (4-methylbenzoyl) cyclopropanecarbonitrile [racemate trans-isomer]

A solution of 4.00 g (26.0 mmol) of the compound from Example 73A in 10 mL of THF is added to 29 ml (28.5 mmol) of a 1N para-toluenemagnesium bromide solution in THF in 70 mL of THF at room temperature under argon and the mixture Was heated at reflux for 2 h. The reaction mixture was added to saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 95/5). 2.60 g (54% of theory) of the title compound were obtained.

Example 127A

2- (2-Chloro-4-fluorobenzoyl) cyclopropanecarbonitrile [racemate trans-isomer]

2.92 g of a solution of 24.0 g (115 mmol) of 2-chloro-4-fluorobromobenzene in 20 mL of diethyl ether in 780 mL of diethyl ether activated by addition of a few drops of dibromoethane ( 120 mmol) was added dropwise to the magnesium pieces and the reaction mixture was heated at reflux overnight. The reaction solution was added dropwise to a solution of 17.7 g (68.8 mmol) of the compound from Example 73A in 300 mL of THF under argon, and the reaction mixture was first stirred at room temperature overnight and then at reflux for 8 hours. It was concentrated, dissolved in ethyl acetate and saturated aqueous ammonium chloride solution, the phases separated, the organic phase washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 2.20 g (14% of theory) of the title compound.

Example 128A

2- (4-Chloro-2-methoxybenzoyl) cyclopropanecarbonitrile [racemate trans-isomer]

A solution of 500 mg (2.26 mmol) of 2-bromo-4-chloroanisole in 5 mL of diethyl ether was added to 57.6 mg of 10 mL of diethyl ether activated by addition of a few drops of dibromoethane ( 2.37 mmol) of magnesium pieces were added dropwise and the reaction mixture was heated at reflux overnight. The reaction solution was added dropwise to a solution of 316 mg (2.05 mmol) of the compound from Example 73A in 10 mL of THF under argon and the reaction mixture was heated at reflux for 2 hours. It was diluted with ethyl acetate and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 9/1) to give 278 mg (58% of theory) of the title compound.

Example 129A

2- [2-fluoro-4- (trifluoromethyl) benzoyl] cyclopropanecarbonitrile [racemate trans-isomer]

2.6 ml (4.12 mmol) of a 1.6N solution of n-butyllithium in hexanes were dissolved in 1.00 g (4.12 mmol) of 1-bromo-2-fluoro-4- (trifluoromethyl) in 8 mL of THF at −78 ° C. ) Was added dropwise to a solution of benzene and the mixture was stirred for 0.5 h. Then a solution of 423 mg (2.74 mmol) of the compound from Example 73A in 2 mL of THF at −78 ° C. was added and the mixture was allowed to come to room temperature and stirred at room temperature for 2 hours. It was diluted with dichloromethane and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 206 mg (29% of theory) of the title compound.

Example 130A

2- (4-Chloro-2-fluorobenzoyl) cyclopropanecarbonitrile [racemate trans-isomer]

0.7 mL of a 0.1N solution of 5.67 g (134 mmol) of lithium chloride and diisobutylaluminum hydride in THF was added to 6.50 g (268 mmol) of magnesium pieces in 30 mL of THF. The mixture is stirred for 5 minutes, cooled to 0 ° C., 22.4 g (107 mmol) of 1-bromo-4-chloro-2-fluorobenzene are added, the mixture is brought to room temperature and stirred at room temperature overnight It was. The reaction solution was added dropwise to a solution of 15.0 g (97.3 mmol) of the compound from Example 73A in 10 mL of THF under argon and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 95/5) to give 5.40 g (25% of theory) of the title compound.

Example 131A

2- (2-fluoro-4-methylbenzoyl) cyclopropanecarbonitrile [racemate trans-isomer]

16.5 ml (26.5 mmol) of a 1.6N solution of n-butyllithium in hexanes are added dropwise to a solution of 5.00 g (26.5 mmol) of 4-bromo-3-fluorotoluene in 40 mL of THF at -78 ° C, and the mixture Stirred for 0.5 h. Then a solution of 2.72 g (17.6 mmol) of the compound from Example 73A in 10 mL of THF at −78 ° C. was added and the mixture was allowed to come to room temperature and stirred at room temperature for 2 hours. Water was added, the mixture was concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added). 300 mg (9% of theory) of the title compound were obtained.

Example 132A

2- {1-hydroxy-1- [4- (trifluoromethyl) phenyl] ethyl} cyclopropanecarbonitrile [trans-diastereomer mixture]

3.0 ml (9.09 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 1.45 g (6.06 mmol) of the compound from Example 122A in 25 mL of diethyl ether at room temperature and the mixture was stirred at room temperature overnight. . The reaction mixture was added to an ice cold saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to afford 1.40 g (90% of theory) of the diastereomer of the title compound.

Example 133A

2- [1- (2,4-difluorophenyl) -1-hydroxyethyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

5.2 ml (15.6 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 2.15 g (10.4 mmol) of the compound from Example 123A in 50 mL of diethyl ether at room temperature and the mixture was stirred at room temperature overnight. . The reaction mixture was added to an ice cold saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 2.16 g (93% of theory) of the diastereomer of the title compound.

Example 134A

1- (4-chlorophenyl) -1- (2,2-difluorocyclopropyl) ethanol

5.7 ml (17.1 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 2.47 g (11.4 mmol) of the compound from Example 124A in 40 mL of diethyl ether at room temperature and the mixture was stirred at room temperature overnight. . The reaction mixture was added to an ice cold saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to afford 2.09 g (78% of theory) of the diastereomer of the title compound.

Example 135A

1-ethyl-5-fluoroindan-1-ol

292 ml (876 mmol) of a 3N solution of ethylmagnesium bromide in diethyl ether are added to 5.00 g (33.3 mmol) of 5-fluoroindan-1-one in 150 mL of diethyl ether at room temperature and the mixture at room temperature. Stir overnight. The reaction mixture was added to an ice cold saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 5.70 g (94% of theory) of the title compound.

Example 136A

1-cyclopropyl-1- [2-fluoro-4- (trifluoromethyl) phenyl] ethanol

A few drops of dibromoethane followed by 6.30 g (52.1 mmol) of cyclopropyl bromide dissolved in 20 mL of diethyl ether were added to 1.33 g (54.7 mmol) of magnesium in 90 mL of dry diethyl ether under argon. . The mixture was heated at reflux for 2 hours. After cooling, 21 ml (9.94 mmol) of the reaction supernatant was removed under argon of 850 mg (4.12 mmol) of 1- [2-fluoro-4- (trifluoromethyl) phenyl] ethanone in 17 mL of diethyl ether. To the solution was added dropwise and the mixture was stirred at rt overnight. The reaction mixture is added to ice water, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient, 0.1% triethylamine added) to give 157 mg (15% of theory) of the diastereomer of the title compound. It was.

Example 137A

1-cyclopropyl-1- (4-methylphenyl) ethanol

27 ml (26.8 mmol) of 1N cyclopropylmagnesium bromide solution in THF are added to 3.00 g (22.4 mmol) of 1- (4-methylphenyl) ethanone in 60 mL of diethyl ether at room temperature and the mixture is stirred at room temperature overnight It was. Then 11 ml (11.2 mmol) of 1N cyclopropylmagnesium bromide solution in additional THF were added and the mixture was stirred at rt overnight. The reaction mixture is added to ice water, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient, 0.1% triethylamine added) to give 491 mg (13% of theory) of the title compound.

Example 138A

1-cyclopropyl-1- (4-chlorophenyl) ethanol

1.50 g (9.70 mmol) of 4-chloroacetophenone was dissolved in 8 mL of diethyl ether at 0 ° C. and 38.8 ml (19.41 mmol) of 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. After stirring at 0 ° C. for 1 hour, warmed to room temperature, water and acetonitrile were added to the reaction solution and the mixture was filtered through diatomaceous earth. The organic solvent was removed on a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and the solvent was removed in vacuo. The crude product was purified twice by preparative HPLC (mobile phase: acetonitrile / water gradient). Acetonitrile was removed from the combined product phases on a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed again with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed in vacuo. 1.37 g (72% of theory) of the title compound were obtained.

Example 139A

1-cyclopropyl-1- [4- (trifluoromethyl) phenyl] ethanol

The title compound was obtained from 1.50 g (7.97 mmol) of 4 '-(trifluoromethyl) acetophenone and 31.9 ml (15.95 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran of the compound from Example 138A. Prepared similarly to the synthesis. 1.27 g (69% of theory) of the title compound were obtained.

Example 140A

1-cyclopropyl-1- (3-fluoro-4-methoxyphenyl) ethanol

The title compound was obtained from 1.50 g (8.92 mmol) of the compound from Example 138A starting from 35.7 ml (17.8 mmol) of 0.5N solution of cyclopropylmagnesium bromide in 3-fluoro-4-methoxyacetophenone and tetrahydrofuran. Prepared similarly to the synthesis. 1.38 g (74% of theory) of the title compound were obtained.

Example 141A

1- (1-benzothiophen-5-yl) -1-cyclopropylethanol

0.60 g (24.64 mmol) of magnesium pieces were dried by heating under argon, cooled to room temperature and 30 mL of tetrahydrofuran was added. 5.00 g (23.46 mmol) of 5-bromo-1-benzothiophene and traces of iodine in 30 mL of tetrahydrofuran were added to the mixture, which was stirred at room temperature for 30 minutes. 2.17 g (25.81 mmol) of acetylcyclopropane in 30 mL of tetrahydrofuran were added and then stirred for 2 hours. The reaction solution was mixed with water and acetonitrile and the mixture was filtered through diatomaceous earth. The organic solvent was removed on a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). Acetonitrile was removed from the combined product phases on a rotary evaporator and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed again with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed in vacuo. 2.39 g (46% of theory) of the title compound were obtained.

Example 142A

1-cyclopropyl-1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethanol

The title compound from Example 138A starting from 1.50 g (8.42 mmol) of 1,4-benzodioxan-6-yl methyl ketone and 33.7 ml (16.84 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran Prepared similar to the synthesis of compounds. 1.12 g (59% of theory) of the title compound were obtained.

Example 143A

1- (1,3-benzodioxol-5-yl) -1-cyclopropylethanol

The title compound was obtained from 1.50 g (9.14 mmol) of 3,4- (methylenedioxy) acetophenone and 36.5 ml (18.28 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran of the compound from Example 138A. Prepared similarly to the synthesis. 1.32 g (70% of theory) of the title compound were obtained.

Example 144A

1-cyclopropyl-1- (2,2-difluoro-1,3-benzodioxol-5-yl) ethanol

15.0 ml of a 0.5N solution of cyclopropylmagnesium bromide in 0.75 g (3.75 mmol) of 1- (2,2-difluoro-1,3-benzodioxol-5-yl) ethanone and tetrahydrofuran Prepared similarly to the synthesis of the compound from Example 138A starting from (7.50 mmol). 0.67 g (74% of theory) of the title compound were obtained.

Example 145A

1-cyclopropyl-1- (4-chlorophenyl) propanol

The title compound was obtained from Example 138A starting from 3.50 g (8.90 mmol) of 1- (4-chlorophenyl) propan-1-one and 35.6 ml (17.79 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran. Prepared similar to the synthesis of compounds. 1.42 g (76% of theory) of the title compound were obtained.

Example 146A

3- (4-chloro-2-fluorophenyl) pentan-3-ol

Synthesis of compound from Example 138A starting with 2.00 g (10.61 mmol) of methyl 4-chloro-2-fluorobenzoate and 31.8 ml (31.82 mmol) of a 1N solution of ethylmagnesium bromide in tetrahydrofuran Similarly prepared. 1.27 g (55% of theory) of the title compound were obtained.

Example 147A

Cyclopropyl (2,4-dichlorophenyl) methanol

17 ml (8.57 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF are added to 1.00 g (5.71 mmol) of 2,4-dichlorobenzaldehyde in 20 mL of diethyl ether at 0 ° C., and the mixture is allowed to warm to room temperature, Stir overnight at room temperature. The reaction mixture is added to water and ethyl acetate, the phases are separated, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water) to give 925 mg (74% of theory) of the title compound.

Example 148A

Cyclopropyl [2-fluoro-4- (trifluoromethyl) phenyl] methanol

31 ml (15.6 mmol) of a 0.5N cyclopropylmagnesium bromide solution in THF were added to 2.00 g (10.4 mmol) of 2-fluoro-4- (trifluoromethyl) benzaldehyde in 40 mL of diethyl ether at 0 ° C, and The mixture was warmed to rt and stirred at rt overnight. The reaction mixture is added to water and ethyl acetate, the phases are separated, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 95/5) to give 1.68 g (69% of theory) of the title compound.

Example 149A

Cyclopropyl [4- (trifluoromethyl) phenyl] methanol

34 ml (17.2 mmol) of a 0.5N cyclopropylmagnesium bromide solution in THF are added to 2.00 g (11.5 mmol) of 4- (trifluoromethyl) benzaldehyde in 44 mL of diethyl ether at 0 ° C. and the mixture is allowed to come to room temperature. Warm and stir overnight at room temperature. The reaction mixture is added to water and ethyl acetate, the phases are separated, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 95/5) to afford 1.77 g (71% of theory) of the title compound.

Example 150A

[2-chloro-4- (trifluoromethyl) phenyl] (cyclopropyl) methanol

84 ml (41.9 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF are added to 5.83 g (30.0 mmol) of 2-chloro-4- (trifluoromethyl) benzaldehyde in 117 mL of diethyl ether at 0 ° C., The mixture was warmed to rt and stirred at rt overnight. The reaction mixture is added to water and ethyl acetate, the phases are separated, the aqueous phase is extracted three times with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 95/5) to afford 5.00 g (61% of theory) of the title compound.

Example 151A

(4-chloro-2-fluorophenyl) (cyclopropyl) methanol

1.00 g (6.31 mmol) of 4-chloro-2-fluorobenzaldehyde were introduced into 20 mL of diethyl ether at 0 ° C., 19 ml (9.46 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF were added, and the mixture was Was stirred at rt overnight. The reaction mixture is added to water, the phases are separated, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water) to give 730 mg (58% of theory) of the title compound.

Example 152A

(2-Chloro-4-methylphenyl) (cyclopropyl) methanol

51.3 mg (1.36 mmol) of sodium borohydride are added to the compound from Example 125A of 320 mg (1.23 mmol) in 5 mL of ethanol and 1 mL of ethyl acetate under argon and the mixture is stirred at 40 ° C. for 2 hours. It was. Then 46.6 mg (1.23 mmol) of sodium borohydride were added and the mixture was stirred at 40 ° C. overnight. The reaction mixture is added to saturated aqueous ammonium chloride solution and diethyl ether, the phases are separated, the aqueous phase is extracted twice with diethyl ether, the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, Filtered and concentrated. 307 mg of the title compound were obtained, which were used without further purification.

Example 153A

Cyclopropyl- (4-chlorophenyl) methanol

1.50 g (10.67 mmol) of 4-chlorobenzaldehyde was dissolved in 20 mL of diethyl ether at 0 ° C. and 32.0 ml (16.00 mmol) of 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. After stirring at 0 ° C. for 1 hour, warmed to room temperature, water and ethyl acetate were added to the reaction solution and the phases were separated. The organic phase is dried over sodium sulphate, the solid is filtered off and the solvent is removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 1.21 g (62% of theory) of the title compound.

Example 154A

Cyclopropyl- (2,4-difluorophenyl) methanol

The title compound is analogous to the synthesis of the compound from Example 153A starting from 1.50 g (10.55 mmol) of 2N 4-solution of cyclopropylmagnesium bromide in 2,4-difluorobenzaldehyde and tetrahydrofuran (31.7 ml (15.83 mmol)) To make. 0.33 g (17% of theory) of the title compound were obtained.

Example 155A

Cyclopropyl- (2-chloro-4-fluorophenyl) methanol

Synthesis of the title compound from Example 153A starting with 28.4 ml (14.19 mmol) of 0.5N solution of cyclopropylmagnesium bromide in 1.50 g (9.46 mmol) of 2-chloro-4-fluorobenzaldehyde and tetrahydrofuran Similarly prepared. 1.51 g (80% of theory) of the title compound were obtained.

Example 156A

(4-chloro-2,6-difluorophenyl) (cyclopropyl) methanol

2.00 g (11.33 mmol) of 4-chloro-2,6-difluorobenzaldehyde are dissolved in 15 mL of diethyl ether at 0 ° C. and 34.0 ml (16.99 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran ) Was slowly added dropwise. After stirring for 2 hours at room temperature, the reaction solution was mixed with 1N hydrochloric acid and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 1.20 g (48% of theory) of the title compound were obtained.

Example 157A

Cyclopropyl (2,2-difluoro-1,3-benzodioxol-5-yl) methanol

Example 156A starting from 3.50 g (18.81 mmol) of 26.4 2-difluoro-5-formylbenzodioxolane and 56.4 ml (28.21 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran Prepared analogously to the synthesis of compounds from. 1.59 (37% of theory) of the title compound were obtained.

Example 158A

2- [hydroxy (4-methylphenyl) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

607 mg (16.0 mmol) of sodium borohydride are added under argon to 2.70 g (14.6 mmol) of the compound from Example 126A in 60 mL of ethanol and 16 mL of ethyl acetate, and the mixture is stirred at 40 ° C. for 2 hours. It was. The reaction mixture was added to water, extracted with dichloromethane and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 2.56 g (94% of theory) of the diastereomer of the title compound.

Example 159A

(4-chlorophenyl) (2,2-difluorocyclopropyl) methanol

336 mg (8.89 mmol) of sodium borohydride are added to 1.75 g (8.08 mmol) of the compound from Example 124A in 33 mL of ethanol and 9 mL of ethyl acetate under argon and the mixture is stirred at 40 ° C. for 1 hour. It was. The reaction mixture is added to saturated aqueous ammonium chloride solution and diethyl ether, the phases are separated, the aqueous phase is extracted twice with diethyl ether, the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate , Filtered and concentrated. 1.44 g (82% of theory) of a mixture of diastereomers of the title compound were obtained.

Example 160A

2- {hydroxy [4- (trifluoromethyl) phenyl] methyl} cyclopropanecarbonitrile [trans-diastereomer mixture]

298 mg (7.88 mmol) of sodium borohydride are added to 1.71 g (7.17 mmol) of the compound from Example 122A in 30 mL of ethanol and 7 mL of ethyl acetate under argon and the mixture is stirred at 40 ° C. for 1 hour. It was. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 1.64 g (95% of theory) of the diastereomer of the title compound.

Example 161A

2-[(2-chloro-4-fluorophenyl) (hydroxy) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

409 mg (10.8 mmol) sodium borohydride are added under argon to 2.20 g (9.84 mmol) of the compound from Example 127A in 180 mL of ethanol and 60 mL of ethyl acetate and the mixture is stirred at 40 ° C. for 2 hours. It was. The reaction mixture is added to dichloromethane, the phases are separated and the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient) to yield 1.52 g (69% of theory) of the diastereomer of the title compound.

Example 162A

2-[(2,4-difluorophenyl) (hydroxy) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

342 mg (9.03 mmol) sodium borohydride are added under argon to 1.70 g (8.21 mmol) of the compound from Example 123A in 35 mL of ethanol and 15 mL of ethyl acetate, and the mixture is stirred at 40 ° C. for 1 hour. It was. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 9/1) to afford 1.50 g (87% of theory) of the diastereomer of the title compound.

Example 163A

2-[(4-chloro-2-methoxyphenyl) (hydroxy) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

49.1 mg (1.30 mmol) of sodium borohydride are added to 278 mg (1.18 mmol) of the compound from Example 128A in 23 mL of ethanol and 10 mL of ethyl acetate under argon and the mixture is stirred at 40 ° C. for 1 hour. It was. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. 190 mg (68% of theory) of a mixture of diastereomers of the title compound were obtained.

Example 164A

2-{[2-fluoro-4- (trifluoromethyl) phenyl] (hydroxy) methyl} cyclopropanecarbonitrile [trans-diastereomer mixture]

351 mg (9.28 mmol) of sodium borohydride are added to 2.17 g (8.44 mmol) of the compound from Example 129A in 38 mL of ethanol and 16 mL of ethyl acetate under argon and the mixture is stirred at 40 ° C. for 1 hour. It was. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 9/1) to afford 1.59 g (73% of theory) of the diastereomer of the title compound.

Example 165A

2-[(4-chloro-2-fluorophenyl) (hydroxy) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

1.01 g (26.6 mmol) of sodium borohydride is added to 5.40 g (24.1 mmol) of the compound from Example 130A in 99 mL of ethanol and 25 mL of ethyl acetate under argon and the mixture is stirred at 40 ° C. for 45 minutes. It was. The reaction mixture is added to saturated aqueous ammonium chloride solution and diethyl ether, the phases are separated, the aqueous phase is extracted twice with diethyl ether, the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, Filtered and concentrated. 5.25 g (96% of theory) of a mixture of diastereomers of the title compound were obtained.

Example 166A

2-[(2-fluoro-4-methylphenyl) (hydroxy) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

61.0 mg (1.62 mmol) of sodium borohydride are added under argon to 300 mg (1.48 mmol) of the compound from Example 131A in 30 mL of ethanol and 13 mL of ethyl acetate, and the mixture is stirred at 40 ° C. for 1 hour. It was. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. 280 mg (92% of theory) of a mixture of diastereomers of the title compound were obtained.

Example 167A

2-[(4-chlorophenyl) (hydroxy) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

736 mg (19.5 mmol) sodium borohydride are added under argon to 4.85 g (17.7 mmol) of the compound from Example 74A in 73 mL of ethanol and 18 mL of ethyl acetate, and the mixture is stirred at 40 ° C. for 2 hours. It was. The reaction mixture is added to saturated aqueous ammonium chloride solution and diethyl ether, the phases are separated, the aqueous phase is extracted twice with diethyl ether, the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, Filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene / ethanol 9/1) to afford 2.79 g (76% of theory) of the diastereomer of the title compound.

Example 168A

3- (3,5-difluorophenoxy) propan-1-ol

2.77 g (69.18 mmol) sodium hydride (60% in mineral oil) was dissolved in 80 mL of DMF. At 0 ° C., after gas evolution stopped, 7.50 g (57.65 mmol) of 3,5-difluorophenol in 15 mL of DMF were added dropwise and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to 0 ° C. and 5.45 g (57.65 mmol) of 3-chloro-1-propanol in 15 mL of DMF were added, then the mixture was stirred at 60 ° C. for 2 hours and stirred at 75 ° C. for 16 hours. It was. The precipitated salt was filtered off and the DMF was removed on a rotary evaporator. The residue was taken up in water and extracted twice with diethyl ether. The combined organic phases were washed successively with water, 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient) to yield 8.15 g (75% of theory) of the title compound.

Example 169A

3- (3,5-difluorophenoxy) propanoic acid

At about −20 ° C., 17.22 g (172.18 mmol) of chromium (VI) was dissolved in 1.2 L of acetone and 38 mL of water and 19 mL of concentrated sulfuric acid was slowly added to the mixture. The mixture was stirred for 10 minutes and then 8.10 g (43.05 mmol) of the compound from Example 168A in 400 mL of acetone was added dropwise over 1 hour. The mixture was stirred at 0 ° C for 1.5 h. After addition of 90 mL of propan-2-ol, the reaction mixture was filtered through diatomaceous earth, the solvent was removed from the filtrate under vacuum and the residue was taken up in 500 mL of diethyl ether. The solution was washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. 11.36 g of the title compound were obtained, which were further reacted in the next step without further purification.

Example 170A

5,7-difluoro-2,3-dihydro-4H-chromen-4-one

0.5 mL of DMF and 7.35 ml (84.29 mmol) of oxalyl chloride were slowly added dropwise to a solution of 11.36 g (42.15 mmol) of the compound from Example 169A in 400 mL of dichloromethane at room temperature. After stirring for 3 hours at room temperature, the solvent was removed on a rotary evaporator and the residue was again dissolved in 200 mL of dichloromethane. 6.74 g (50.57 mmol) of aluminum trichloride were added portionwise to the reaction mixture and the mixture was stirred for 1 hour. 150 mL of 2N hydrochloric acid and 200 mL of dichloromethane were added, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 6.46 g (80% of theory) of the title compound were obtained.

Example 171A

5,7-difluoro-4-methyl-3,4-dihydro-2H-chromen-4-ol

2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 mL of diethyl ether at 0 ° C. and 5.4 ml (16.29 mmol) of 3N solution of methylmagnesium bromide in diethyl ether were slowly added dropwise. After stirring for 1 hour at 0 ° C., warmed to room temperature, water and diethyl ether were added to the reaction solution and the phases were separated. The aqueous phase was extracted with diethyl ether and the combined organic phases were dried over sodium sulphate and filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound were obtained.

Example 172A

4-cyclopropyl-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol

2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 mL of diethyl ether at 0 ° C. and 32.6 ml (16.29 mmol) of 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. After stirring for 1 hour at 0 ° C., warmed to room temperature, water and diethyl ether were added to the reaction solution and the phases were separated. The aqueous phase was extracted with diethyl ether and the combined organic phases were dried over sodium sulphate and filtered and the solvent removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). Acetonitrile was removed from the combined product phases on a rotary evaporator and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered and the solvent removed in vacuo. 0.66 g (27% of theory) of the title compound were obtained.

Example 173A

4-[(4-fluorophenyl) (hydroxy) methyl] benzonitrile

5.00 g (28.57 mmol) of 4-fluorobromobenzene were dissolved in 100 ml tetrahydrofuran at -78 ° C. 21.4 ml (34.29 mmol) of a 1.6N solution of n-butyllithium in hexane were added, followed by stirring for 15 minutes, and then 4.50 g (34.29 mmol) of 4-cyanobenzaldehyde dissolved in 30 mL of tetrahydrofuran. Added. The mixture was stirred at -78 ° C for 1 hour, warmed to room temperature and then stirred for 1 hour. The reaction solution was mixed with water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and the solid was filtered off. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). Acetonitrile was removed from the product-containing fractions on a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of the solvent gave 2.37 g (36% of theory) of the title compound.

Example 174A

4-[(4-chlorophenyl) (hydroxy) methyl] benzonitrile

0.67 g (27.42 mmol) of magnesium pieces were dried by heating under argon, cooled to room temperature, and then 30 mL of tetrahydrofuran and 2 mL of dibromoethane were added. At 0 ° C., 5.00 g (26.12 mmol) of 4-chlorobromobenzene in 30 mL of tetrahydrofuran were slowly added to the mixture and the mixture was stirred at room temperature for 30 minutes. 3.77 g (28.73 mmol) of 4-cyanobenzaldehyde in 30 mL of tetrahydrofuran were added and then stirred for 3 hours. THF was removed from the reaction solution on a rotary evaporator and the residue was taken up in dichloromethane. It was washed with 1N hydrochloric acid, dried over sodium sulfate, filtered and the solvent removed in vacuo. The precipitate separated from the oily residue was filtered off, washed with diethyl ether and purified by preparative HPLC (mobile phase: acetonitrile / water gradient). Acetonitrile was removed from the product-containing fractions on a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of solvent gave 1.43 g (23% of theory) of the title compound.

Example 175A

(4-chlorophenyl) (4-methoxyphenyl) methanol

5.00 g (26.12 mmol) of 4-chlorobromobenzene were dissolved in 100 mL of tetrahydrofuran at -78 ° C. 19.6 ml (31.34 mmol) of a 1.6N solution of n-butyllithium in hexane were added, followed by stirring for 15 minutes, followed by 4.27 g (31.34 mmol) of 4-methoxybenzaldehyde dissolved in 30 mL of tetrahydrofuran. Added dropwise. The mixture was stirred at -78 ° C for 1 hour, warmed to room temperature and then stirred for 1 hour. The reaction solution was mixed with water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and the solid was filtered off. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). Acetonitrile was removed from the product-containing fractions on a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of the solvent gave 4.20 g (65% of theory) of the title compound.

Example 176A

(4-chloro-3-fluorophenyl) (4-fluorophenyl) methanol

The title compound was prepared analogously to the synthesis of the compound from Example 175A starting from 5.00 g (28.57 mmol) 4-fluorobromobenzene and 5.44 g (34.29 mmol) 3-fluoro-4-chlorobenzaldehyde. 5.01 g (69% of theory) of the title compound were obtained.

Example 177A

(3-chloro-4-fluorophenyl) (4-chlorophenyl) methanol

The title compound was prepared analogously to the synthesis of the compound from Example 175A starting from 5.00 g (26.12 mmol) 4-chlorobromobenzene and 4.97 g (31.34 mmol) 4-fluoro-3-chlorobenzaldehyde. 5.57 g (77% of theory) of the title compound were obtained.

Example 178A

(4-chloro-2,6-difluorophenyl) (4-fluorophenyl) methanol

5.00 g (21.98 mmol) of 2-bromo-5-chloro-1,3-dibromobenzene was dissolved in 100 mL of tetrahydrofuran at -78 ° C. 16.5 ml (26.38 mmol) of a 1.6N solution of n-butyllithium in hexane were added, followed by stirring for 15 minutes, followed by 3.27 g (26.38 mmol) of 4-fluorobenzaldehyde dissolved in 30 mL of tetrahydrofuran. Added dropwise. The mixture was stirred at -78 ° C for 1 hour, warmed to room temperature and then stirred for 1 hour. The reaction solution was mixed with water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and the solid was filtered off. The solvent was removed in vacuo and the crude product was purified twice by preparative HPLC (mobile phase: acetonitrile / water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 4/1). . The solvent was removed from the product-containing fractions on a rotary evaporator and the aqueous residue was extracted with dichloromethane. Removal of solvent gave 0.80 g (13% of theory) of the title compound.

Example 179A

Bis (4-chloro-2-fluorophenyl) methanol

The title compound is similar to the synthesis of the compound from Example 175A starting from 5.00 g (23.87 mmol) 4-chloro-2-fluorobromobenzene and 4.54 g (28.65 mmol) 4-chloro-2-fluorobenzaldehyde To make. The difference is that preliminary separation by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient) is carried out before the crude product is purified by preparative HPLC. 1.79 g (26% of theory) of the title compound were obtained.

Example 180A

(4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methanol

The title compound is similar to the synthesis of a compound from Example 175A starting from 5.00 g (26.45 mmol) 2-bromo-5-fluorotoluene and 5.03 g (31.74 mmol) 4-chloro-2-fluorobenzaldehyde To make. The difference is that the crude product is purified twice by preparative HPLC. 4.84 g (65% of theory) of the title compound were obtained.

Example 181A

(4-chloro-2-fluorophenyl) (2,4-difluorophenyl) methanol

The title compound is analogous to the synthesis of the compound from Example 175A starting from 5.00 g (25.91 mmol) of 2,4-difluorobromobenzene and 4.93 g (31.09 mmol) of 4-chloro-2-fluorobenzaldehyde Prepared. 3.34 g (47% of theory) of the title compound were obtained.

Example 182A

1- (4-chlorophenyl) -1- (4-fluorophenyl) ethanol

The title compound was prepared analogously to the synthesis of the compound from Example 176A starting from 5.00 g (28.57 mmol) 4-bromofluorobenzene and 4.86 g (31.43 mmol) 4-chloroacetophenone. The difference is that preliminary separation by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 9/1) is carried out before the crude product is purified by preparative HPLC. 5.23 g (73% of theory) of the title compound were obtained.

Example 183A

1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethanol

The title compound is prepared analogously to the synthesis of the compound from Example 176A starting from 4.22 g (24.14 mmol) 4-bromofluorobenzene and 5.00 g (28.97 mmol) 4-chloro-2-fluoroacetophenone It was. The difference is that the crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 9/1). 5.23 g (73% of theory) of the title compound were obtained.

Example 184A

1- [4- (trifluoromethyl) phenyl] prop-2-en-1-ol

A solution of 75.0 g (431 mmol) of 4- (trifluoromethyl) benzaldehyde in 750 mL of diethyl ether was slowly added dropwise to 517 ml (517 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran at room temperature under argon. . After heating for 1 hour under reflux, the reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The organic phase was dried, filtered and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: petroleum ether / ethyl acetate 9/1) to give 87.0 g (100% of theory) of the title compound.

Example 185A

1- (2,4-dichlorophenyl) prop-2-en-1-ol

A solution of 20.0 g (114 mmol) of 2,4-dichlorobenzaldehyde in 200 mL of diethyl ether was slowly added dropwise to 137 ml (137 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran under argon at room temperature. After heating under reflux for 1 hour, the reaction mixture was added to saturated aqueous ammonium chloride solution and diluted with diethyl ether and water. The phases were separated and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5/1) to afford 18.8 g (81% of theory) of the title compound.

Example 186A

1- [4- (trifluoromethyl) phenyl] prop-2-en-1-one

A solution of 18.0 g (89.0 mmol) of the compound from Example 184A in 360 mL of dichloromethane was added to 45.3 g (107 mmol) of 1,1,1-triacetoxy-1,1 in 360 mL of dichloromethane at room temperature. -Dropwise to a solution of dihydro-1,2-benziodoxol-3 (1H) -one. After stirring for 1 hour at room temperature, the reaction mixture was added to a mixture of saturated aqueous sodium bicarbonate solution and sodium thiosulfate and extracted three times with dichloromethane. The organic phase was dried, filtered and concentrated. 17.5 g (98% of theory) of the title compound were obtained.

Example 187A

1- (2,4-dichlorophenyl) prop-2-en-1-one

73.5 g (362 mmol) of the compound from Example 185A in 2.2 L of dichloromethane were mixed with 105 g (1.21 mol) of activated manganese dioxide and heated at reflux for 20 hours. An additional 105 g (1.21 mol) of activated manganese dioxide in each case were added after 2 hours and after 4 hours. Filter by suction through diatomaceous earth, wash with dichloromethane and concentrate to give 57.0 g of a mixture of the title compound and the compound from Example 185A. 47.7 g (162 mmol) of potassium dichromate was added to 47.0 g of the mixture in sulfuric acid at 329 mL of 10% concentration, sometimes cooled at 15-20 ° C. and the mixture was stirred for 1.5 hours. Then 400 mL of ethyl acetate was added, neutralized by addition of sodium bicarbonate, filtered through diatomaceous earth, washed with ethyl acetate, the phases were separated, the organic phase dried and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 6/1) to give 17.8 g (55%) of the title compound.

Example 188A

2,2-difluorocyclopropyl) [4- (trifluoromethyl) phenyl] methanone

10.0 g (50.0 mmol) of the compound from Example 186A is stirred with 210 mg (5.00 mmol) sodium fluoride for 5 minutes under argon at 110 ° C., and 25.0 g (99.9 mmol) trimethylsilyl 2,2-di Fluoro-2- (fluorosulfonyl) acetate was slowly added in small portions and the mixture was stirred at 110 ° C. for 20 minutes. The reaction mixture was then mixed with saturated aqueous sodium bicarbonate solution and ethyl acetate, the phases were separated, and the organic phase was dried and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 4/1) to give 6.80 g (54% of theory) of the title compound.

Example 189A

(2,4-dichlorophenyl) (2,2-difluorocyclopropyl) methanone

The title compound was prepared analogously to the synthesis of the compound from Example 188A starting from 20.0 g (99.5 mmol) of the compound from Example 187A. 13.4 g (54% of theory) of the title compound were obtained.

Example 190A

(2,2-difluorocyclopropyl) [4- (trifluoromethyl) phenyl] methanol

1.13 g (29.9 mmol) of sodium borohydride are added to a solution of 6.80 g (27.2 mmol) of the compound from Example 188A in 111 mL of ethanol and 29 mL of ethyl acetate under argon and the mixture is stirred at 40 ° C. for 1 hour. Was stirred. The reaction mixture was then added to ethyl acetate and saturated aqueous ammonium chloride solution and stirred for 10 minutes. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 4/1) to give 2.50 g (37% of theory) of the title compound as a mixture of diastereomers.

Example 191A

(2,4-dichlorophenyl) (2,2-difluorocyclopropyl) methanol

The title compound was prepared analogously to the synthesis of the compound from Example 190A starting from 9.00 g (35.8 mmol) of the compound from Example 189A. 7.30 g (80% of theory) of the diastereomer 1 of the title compound and 1.10 g (12% of the theory) of the diastereomer 2 of the title compound were obtained.

Diastereomer 191A-1:

Diastereomer 191A-2:

Example 192A

(2,2-difluorocyclopropyl) [4- (trifluoromethyl) phenyl] methyl acetate

0.23 ml (2.86 mmol) pyridine was added dropwise to 2.40 g (9.52 mmol) of the compound from Example 190A and 1.94 g (19.0 mmol) acetic anhydride and the mixture was stirred at rt overnight. The reaction mixture was then added to ethyl acetate and saturated aqueous sodium bicarbonate solution. The phases were separated, the organic phase was concentrated and the crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 6/1). 2.66 g (95% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 193A

(2,4-dichlorophenyl) (2,2-difluorocyclopropyl) methyl acetate

The title compound was prepared analogously to the synthesis of the compound from Example 192A starting from 8.20 g (32.4 mmol) of a mixture of the two diastereomers of the compound from Example 191A. 7.70 g (81% of theory) of the title compound were obtained.

Exemplary Embodiments:

Example 1

3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propan-1-ol

A solution of 215 mg (0.51 mmol) of the compound from Example 25A was added dropwise to 1.8 ml (1.80 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 10 mL of tetrahydrofuran under argon at room temperature. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added while cooling on ice. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient) gave 169 mg (87% of theory) of the title compound.

Example 2

3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 6.68 g (17.2 mmol) of the compound from Example 29A in 100 mL of tetrahydrofuran 60 ml (60 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 300 mL of tetrahydrofuran under argon at room temperature Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added while cooling on ice. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient). 5.93 g (99% of theory) of the desired compound were obtained.

Example 3

3- (4-chlorophenyl) -3- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 1.05 g (2.19 mmol) of the compound from Example 33A in 84% purity in 20 mL tetrahydrofuran 9.1 ml 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 mL tetrahydrofuran under argon at room temperature (9.1 mmol) dropwise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added while cooling on ice. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 0.95 g (94% of theory) of the title compound.

Example 4

3- (4-chloro-2-fluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

19.2 ml (19.2 mmol) of a solution of lithium aluminum hydride in tetrahydrofuran in 50 mL of tetrahydrofuran under argon at room temperature in a solution of 2.23 g (5.49 mmol) of compound from Example 34A in 20 mL of tetrahydrofuran. Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 1.89 g (95% of theory) of the title compound.

Enantiomer 4-1:

2.20 g (4.88 mmol) of 90% purity enantiomer 34A-2 was reacted analogously to the synthesis of the compound from Example 4. 1.50 g (85% of theory) of the title compound were obtained.

Example 5

3- (4-chloro-2-fluorophenyl) -2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 200 mg (0.35 mmol) of the compound from Example 36A in 90% purity in 4 mL of tetrahydrofuran 1.2 ml of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 2 mL of tetrahydrofuran under argon at room temperature (1.2 mmol) dropwise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 66 mg (51% of theory) of the title compound as a mixture of diastereomers. .

Example 6

3- (4-chloro-2-fluorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

9.0 ml (9.0 mmol) of a 1 N solution of lithium aluminum hydride in tetrahydrofuran in 50 mL tetrahydrofuran under argon at room temperature in a solution of 1.1 g (2.57 mmol) of compound from Example 37A in 20 mL tetrahydrofuran. Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 715 mg (73% of theory) of the title compound.

Example 7

3- (2,4-dichlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

19.4 ml (19.4 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 mL of tetrahydrofuran under argon at room temperature in a solution of 2.34 g (5.54 mmol) of compound from Example 38A in 20 mL of tetrahydrofuran Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to afford 2.00 g (95% of theory) of the title compound.

Example 8

3- (2,4-dichlorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

11.8 ml (11.8 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 mL of tetrahydrofuran under argon at room temperature in a solution of 1.48 g (3.36 mmol) of compound from Example 39A in 20 mL tetrahydrofuran Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate, filtered and concentrated. 1.32 g (99% of theory) of the title compound were obtained.

Example 9

3- (4-chlorophenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

11.1 ml of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 70 mL tetrahydrofuran under argon at room temperature with a solution of 1.29 g (2.52 mmol) of 79% purity in 30 mL tetrahydrofuran at 79% purity. (11.1 mmol) dropwise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to yield 0.68 g (74% of theory) of the title compound.

Example 10

3- (4-chloro-2-methylphenyl) -3- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

5.7 ml (5.7 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 mL of tetrahydrofuran under argon at room temperature in a solution of 2.23 g (5.49 mmol) of compound from Example 41A in 20 mL of tetrahydrofuran. Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 458 mg (76% of theory) of the title compound.

Example 11

3- (4-chloro-2-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

The title compound was prepared analogously to the synthesis of the compound from Example 4 starting from 1.62 g (4.03 mmol) of the compound from Example 42A. 1.4 g (97% of theory) of the title compound were obtained.

Example 12

3- (4-fluoro-2-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

5.3 ml (5.31 mmol) of a solution of lithium aluminum hydride in tetrahydrofuran in 30 mL of tetrahydrofuran under argon at room temperature in a solution of 585 mg (1.52 mmol) of the compound from Example 43A in 15 mL of tetrahydrofuran. Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added while cooling on ice. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 369 mg (71% of theory) of the title compound.

Example 13

3- [2-fluoro-4- (trifluoromethyl) phenyl] -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 2.74 g (6.13 mmol) of the compound from Example 44A in 20 mL of tetrahydrofuran was dissolved in 21.5 ml (21.5 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 mL of tetrahydrofuran under argon at room temperature. Was added drop wise. After stirring at room temperature for 15 minutes, 1N hydrochloric acid is added, extracted with dichloromethane, and the organic phase is dried over magnesium sulphate, filtered and concentrated. 2.47 g (99% of theory) of the title compound were obtained.

Example 14

3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- (naphthalen-2-yl) propan-1-ol

A solution of 600 mg (1.49 mmol) of the compound from Example 45A in 15 mL of tetrahydrofuran 5.2 ml (5.2 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 30 mL of tetrahydrofuran under argon at room temperature Was added drop wise. After stirring at room temperature for 15 minutes, while cooling on ice, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. 486 mg (90% of theory) of the title compound were obtained.

Example 15

4- (4-chlorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butan-1-ol

A solution of 420 mg (1.05 mmol) of the compound from Example 46A in 10 mL of tetrahydrofuran 3.7 ml (3.7 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 20 mL of tetrahydrofuran under argon at room temperature Was added drop wise. The mixture was stirred at rt for 15 min, then 1N hydrochloric acid was added while cooling on ice. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added). 243 mg (65% of theory) of the desired compound were obtained.

Example 16

3- (4-chlorophenyl) -3- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 2.33 g (5.7 mmol) of the compound from Example 47A in 18 mL of tetrahydrofuran was added dropwise to 20.1 ml (60.1 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran and 20 mL of tetrahydrofuran at room temperature. . The mixture was stirred at 60 ° C. for 1 h, acetonitrile was added and water was added to the solution while cooling on ice. The solid was filtered off with suction from the suspension, the filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 1.72 g (82% of theory) of the title compound were obtained.

Example 17

3- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propan-1-ol

The title compound was prepared analogously to the synthesis of the compound from Example 16 starting from 2.98 g (6.78 mmol) of the compound from Example 48A. 2.47 g (92% of theory) of the title compound were obtained.

Example 18

3- (1-benzothiophen-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

The title compound was prepared analogously to the synthesis of the compound from Example 16 starting from 1.17 g (2.87 mmol) of the compound from Example 49A. 0.93 g (88% of theory) of the title compound were obtained.

Example 19

3- (2-bromo-1,3-thiazol-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 1.19 g (2.71 mmol) of the compound from Example 50A in 25 mL of tetrahydrofuran was subjected to 8.13 ml (8.13 mmol) of 1N solution of diisobutylaluminum hydride in heptane / tetrahydrofuran and tetrahydrofuran at room temperature. Add dropwise to 25 mL. The mixture was stirred at rt for 1 h and the solution was mixed with ethyl acetate, water and 1N hydrochloric acid. The phases were separated, the aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. Then it was dried over sodium sulfate, the solids were removed by filtration and the solvents were removed from the crude product under vacuum. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 0.73 g (68% of theory) of the title compound.

Example 20

2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] propan-1-ol

The title compound was prepared analogously to the synthesis of the compound from Example 19 starting from 0.97 g (2.23 mmol) of the compound from Example 28A. 0.66 g (75% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 21

3- (4-chlorophenyl) -2-methyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

The title compound was prepared analogously to the synthesis of the compound from Example 19 from 395 mg (0.98 mmol) of the compound from Example 32A. 222 mg (63% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 22

3- (4-chloro-2-fluorophenyl) -3- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

60 mg (0.16 mmol) of the compound from Example 6 were introduced into 2 mL of dichloromethane at 0 ° C., 79.4 mg (0.32 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 27 mg (42% of theory) of the title compound.

Example 23

3- (2,4-dichlorophenyl) -3- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

100 mg (0.26 mmol) of the compound from Example 7 were introduced into 15 mL of dichloromethane at 0 ° C., 130 mg (0.53 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 50 mg (46% of theory) of the title compound.

Example 24

3- (2,4-dichlorophenyl) -3- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

100 mg (0.25 mmol) of the compound from Example 8 were introduced into 15 mL of dichloromethane at 0 ° C., 124 mg (0.50 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 51 mg (47% of theory) of the title compound.

Example 25

3- (4-chlorophenyl) -3- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

75.0 mg (0.21 mmol) of the compound from Example 9 were introduced into 12 mL of dichloromethane at 0 ° C., 102 mg (0.41 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 42 mg (52% of theory) of the title compound.

Example 26

3- (4-chloro-2-methylphenyl) -3- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

100 mg (0.28 mmol) of the compound from Example 11 were introduced into 15 mL of dichloromethane at 0 ° C., 137 mg (0.56 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 40 mg (37% of theory) of the title compound.

Example 27

4- (4-chlorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butan-1-ol

40 mg (0.11 mmol) of the compound from Example 15 were introduced into 7 mL of dichloromethane at 0 ° C., 54.8 mg (0.22 mmol) of 70% pure meta-chloroperbenzoic acid was added, and the mixture was allowed to come to room temperature. Stir overnight and then under reflux for 15 minutes. 2 mL of methanol is added, the mixture is concentrated, the residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase is twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was washed, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 20 mg (46% of theory) of the title compound.

Example 28

3- (1-benzothiophen-5-yl) -3- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

100 mg (0.27 mmol) of the compound from Example 18 were introduced into 19 mL of dichloromethane at 0 ° C., 134 mg (0.54 mmol) of 70% pure meta-chloroperbenzoic acid was added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and then the solvent was removed in vacuo. The crude product was purified three times by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 23 mg (21% of theory) of the title compound.

Example 29

3- (4-chlorophenyl) -2-methyl-3- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

The title compound was prepared analogously to the synthesis of the compound from Example 28 starting from 57 mg (0.15 mmol) of the compound from Example 21. 46 mg (77% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 30

3- (4-chloro-2-fluorophenyl) -3- {5-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} propan-1-ol

60 mg (0.16 mmol) of the compound from Example 6 were introduced into 2 mL of dichloromethane at 0 ° C., 40.7 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid was added) to give 29 mg (46% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 31

3- (2,4-dichlorophenyl) -3- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} propan-1-ol

75.9 mg (0.20 mmol) of the compound from Example 7 were introduced into 11 mL of dichloromethane at 0 ° C., 49.2 mg (0.20 mmol) of 70% pure meta-chloroperbenzoic acid was added, and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 50 mg (63% of theory) of the title compound as a mixture of diastereomers. .

Example 32

3- (2,4-dichlorophenyl) -3- {5-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} propan-1-ol

100 mg (0.25 mmol) of the compound from Example 8 were introduced into 15 mL of dichloromethane at 0 ° C., 61.9 mg (0.25 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 91 mg (88% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 33

3- (4-chlorophenyl) -3- {5-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} propan-1-ol

75.0 mg (0.21 mmol) of the compound from Example 9 were introduced into 12 mL of dichloromethane at 0 ° C., 50.8 mg (0.21 mmol) of 70% pure meta-chloroperbenzoic acid was added and the mixture was allowed to come to room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 25 mg (30% of theory) of the title compound. It was contaminated with meta-chlorobenzoic acid. It was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to give 23 mg (29% of theory) of the title compound as a mixture of diastereomers.

Example 34

4- (4-chlorophenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butan-1-ol

40 mg (0.11 mmol) of the compound from Example 15 were introduced into 7 mL of dichloromethane at 0 ° C., 27.4 mg (0.11 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to stand at room temperature. Stir overnight. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 33 mg (79% of theory) of the title compound as a mixture of diastereomers. .

Example 35

4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

28.5 g (0.44 mmol) of potassium cyanide were added to 100 mg (0.22 mmol) of the compound from Example 51A in 5 mL of DMF. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, 0.1% formic acid added) afforded 77 mg (91% of theory) of the title compound.

Example 36

4- (4-chlorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

2.12 g (32.5 mmol) potassium cyanide was added to 6.90 g (16.3 mmol) of the compound from Example 52A in 345 mL of DMF. The mixture was stirred at 80 ° C. for 4 hours, then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate gradient). 5.05 g (87% of theory) of the desired compound were obtained.

Example 37

4- (4-chlorophenyl) -4- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

152 mg (2.33 mmol) of potassium cyanide were added to 510 mg (1.16 mmol) of the compound from Example 53A in 7 mL of DMF. The mixture is stirred at 80 ° C. for 2 hours, cooled, then water is added, the mixture is extracted with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated I was. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added). 222 mg (52% of theory) of the desired compound were obtained.

Example 38

4- (4-chloro-2-fluorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

572 mg (8.78 mmol) potassium cyanide was added to 1.94 g (4.39 mmol) of the compound from Example 54A in 26 mL of DMF. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid), 1.30 g (theoretical value of 79%) of the title compound were obtained.

Enantiomer 38-1:

554 mg (8.51 mmol) potassium cyanide was added to 1.88 g (4.25 mmol) enantiomer 54A-1 in 95 mL of DMF. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added). 727 mg (46% of theory) of the corresponding enantiomer of the title compound were obtained.

Example 39

4- (4-chloro-2-fluorophenyl) -3-methyl-4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

16.2 mg (0.25 mmol) of potassium cyanide were added to 70 mg (0.12 mmol) of the compound from Example 55A in 3 mL of DMSO. The mixture was stirred at 80 ° C. for 4 hours, then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added). 33.4 mg (69% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 40

4- (4-chloro-2-fluorophenyl) -4- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

190 mg (2.91 mmol) potassium cyanide and 8.9 mg (0.07 mmol) 4-N, N-dimethylaminopyridine were added to 670 mg (1.46 mmol) of the compound from Example 56A in 40 mL of DMSO. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 522 mg (92% of theory) of the title compound.

Example 41

4- (2,4-dichlorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

563 mg (8.64 mmol) of potassium cyanide were added to 1.98 g (4.32 mmol) of the compound from Example 57A in 26 mL of DMF. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid), 1.42 g of theory 84%) of the title compound were obtained.

Example 42

4- (2,4-dichlorophenyl) -4- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

1.36 g (2.86 mmol) of the compound from Example 58A and 372 mg (5.71 mmol) of potassium cyanide were dissolved in 65 mL of DMSO and stirred at 120 ° C. overnight. The mixture was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 790 mg (68% of theory) of the title compound.

Example 43

4- (4-chlorophenyl) -4- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

445 mg (1.01 mmol) of the compound from Example 59A and 131 mg (2.01 mmol) of potassium cyanide were dissolved in 23 mL of DMF and stirred at 80 ° C. for 3 days. The mixture was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 102 mg (27% of theory) of the title compound. 180 mg (0.47 mmol) of 3- [3-chloro-1- (4-chlorophenyl) propyl] -5-fluoro-7-[(methylsulfanyl) methyl] -1 H-indole were also obtained.

180 mg (0.47 mmol) 3- [3-chloro-1- (4-chlorophenyl) propyl] -5-fluoro-7-[(methylsulfanyl) methyl] -1H-indole and 61.3 mg (0.94 mmol) ) Potassium cyanide was dissolved in 11 mL of DMSO and stirred at 120 ° C. overnight. The mixture was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford an additional 140 mg (80% of theory) of the title compound. Overall yield was 242 mg (64% of theory).

Example 44

4- (4-chloro-2-methylphenyl) -4- {7-[(ethylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

86.4 mg (1.33 mmol) of potassium cyanide were added to 300 mg (0.66 mmol) of the compound from Example 60A in 4 mL of DMF. After stirring at 80 ° C. for 2 hours, water was added, extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 207 mg (81% of theory) of the title compound.

Example 45

4- (4-chloro-2-methylphenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

419 mg (6.44 mmol) of potassium cyanide were added to 1.41 g (3.22 mmol) of the compound from Example 61A in 20 mL of DMF. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to 987 mg (of theory). 83%) of the title compound were obtained.

Example 46

4- (4-fluoro-2-methylphenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

90.8 mg (1.40 mmol) potassium cyanide was added to 294 mg (0.70 mmol) of the compound from Example 62A in 15 mL of DMF. The mixture was stirred at 80 ° C. for 4 hours, then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 188 mg (77% of theory) of the title compound.

Example 47

4- [2-fluoro-4- (trifluoromethyl) phenyl] -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

726 mg (11.1 mmol) of potassium cyanide were added to 2.65 g (5.57 mmol) of the compound from Example 63A in 128 mL of DMF. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 1.46 g of the title compound were obtained at a purity of 85% (55% of theory).

Example 48

4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -4- (naphthalen-2-yl) butanonitrile

97.5 mg (1.50 mmol) of potassium cyanide were added to 329 mg (0.75 mmol) of the compound from Example 64A in 15 mL of DMF. The mixture was stirred at 80 ° C. for 4 hours, then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 181 mg (65% of theory) of the title compound.

Example 49

5- (4-chlorophenyl) -5- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} pentanonitrile

91.9 mg (1.41 mmol) potassium cyanide was added to 309 mg (0.71 mmol) of the compound from Example 65A in 5 mL of DMF. The mixture was stirred at 80 ° C. for 2 hours, then concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added). The crude product was dissolved in dichloromethane to remove DMF, washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 134 mg (52% of theory) of the desired compound were obtained.

Example 50

4- (4-chlorophenyl) -4- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

0.46 g (7.01 mmol) of potassium cyanide was added to 1.55 g (3.50 mmol) of the compound from Example 66A in 32 mL of DMF. The mixture was stirred at 80 ° C. for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were dried over sodium sulphate, the solid was filtered off and the solvent was removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 1.00 g (77% of theory) of the desired compound were obtained.

Example 51

4- {6-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 50 starting from 2.20 g (4.62 mmol) of the compound from Example 67A. 1.66 g (88% of theory) of the target compound were obtained.

Example 52

4- (1-benzothiophen-5-yl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 50 starting from 768 mg (1.72 mmol) of the compound from Example 68A. 494 mg (76% of theory) of the desired compound were obtained.

Example 53

4- (2-bromo-1,3-thiazol-5-yl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

14 mg (0.21 mmol) of potassium cyanide were added to 50 mg (0.11 mmol) of the compound from Example 69A in 1 mL of DMF. The mixture was stirred at 80 ° C. for 5 h, water was added to the reaction solution and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, the solid was filtered off and the solvent was removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 38 mg (89% of theory) of the target compound were obtained.

Example 54

3-methyl-4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

The title compound was prepared similar to the synthesis of the compound from Example 53 starting from 620 mg (1.32 mmol) of the compound from Example 70A, but using dimethyl sulfoxide as the solvent. 492 mg (93% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 55

4- (4-chlorophenyl) -3-methyl-4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

The title compound was prepared similar to the synthesis of the compound from Example 53 starting from 215 mg (0.49 mmol) of the compound from Example 71A, but using dimethyl sulfoxide as the solvent. 177 mg (98% of theory) of the target compound were obtained as a mixture of diastereomers.

Example 56

4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

100 mg (0.26 mmol) of the compound from Example 35 were introduced into 20 mL of dichloromethane at 0 ° C., 159 mg (0.64 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, 0.1% formic acid added) to give 51 mg (47% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 6: 4; Flow rate: 20 ml / min; Temperature: 22 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added):

Enantiomer 56-1:

R _t = 6.86 min [Column: Daicel AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / isopropanol 6: 4; Flow rate: 1.0 ml / min; Temperature: 23 ° C .; UV detection: 230 nm];

Yield: 7.1 mg

Enantiomer 56-2:

R _t = 7.71 min [Column: Daicel AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / isopropanol 6: 4; Flow rate: 1.0 ml / min; Temperature: 22 ° C .; UV detection: 230 nm].

Yield: 9.6 mg

Example 57

4- (4-chlorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

3.00 g (8.45 mmol) of the compound from Example 36 were introduced into 600 mL of dichloromethane at 0 ° C., 2.08 g (8.45 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to stand at room temperature. Stir overnight. 20 mL of methanol was added and the mixture was extracted with water and saturated aqueous sodium bicarbonate solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 205 mg (6% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 3: 7; Flow rate: 25 ml / min; Temperature: 26 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added):

Enantiomer 57-1:

R _t = 6.93 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm];

Yield: 50 mg

Enantiomer 57-2:

R _t = 7.82 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm];

Yield: 54 mg

Example 58

4- (4-chlorophenyl) -4- {7-[(ethylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

83.0 mg (0.23 mmol) of the compound from Example 37 were introduced into 13 mL of dichloromethane at 0 ° C., 111 mg (0.45 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 43.5 mg (48% of theory) of the title compound.

Example 59

4- (4-chloro-2-fluorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

660 mg (1.77 mmol) of the compound from Example 38 were introduced into 99 mL of dichloromethane at 0 ° C., 873 mg (3.54 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. 20 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and concentrated I was. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 620 mg (87% of theory) of the title compound.

Enantiomers 59-1:

600 mg (1.61 mmol) of enantiomer 38-1 were introduced into 20 mL of dichloromethane at 0 ° C., 813 mg (3.30 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to stand at room temperature overnight. Stirred. The residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 450 mg (69% of theory) of the corresponding enantiomer of the title compound. Obtained.

Example 60

4- (4-chloro-2-fluorophenyl) -3-methyl-4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

30.0 mg (0.08 mmol) of the compound from Example 39 were introduced into 2 mL of dichloromethane at room temperature, 39.2 mg (0.16 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was overnight at room temperature. Stirred. 1 mL of methanol is added and the residue is concentrated and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added), 9 mg (28% of theory) The diastereomers 60-1 and 16.1 mg (50% of theory) of the title compound were obtained diastereomer 60-2 of the title compound.

Diastereomer 60-1:

Diastereomer 60-2:

Example 61

4- (4-chloro-2-fluorophenyl) -4- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

80.0 mg (0.21 mmol) of the compound from Example 40 were introduced into 5 mL of dichloromethane at 0 ° C., 103 mg (0.42 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir overnight. Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to 46 mg (53% of theory) of the title compound. Obtained.

Example 62

4- (2,4-dichlorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

200 mg (0.51 mmol) of the compound from Example 41 were introduced into 30 mL of dichloromethane at 0 ° C., 253 mg (1.03 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol was added and the residue was concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution and the phases were separated. The organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 136 mg (63% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 7: 3; Flow rate: 20 ml / min; Temperature: RT; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added):

Enantiomer 62-1:

R _t = 18.55 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 4: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm];

Enantiomer 62-2:

R _t = 20.07 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 4: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm].

Example 63

4- (2,4-dichlorophenyl) -4- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

590 mg (1.45 mmol) of the compound from Example 42 were introduced into 85 mL of dichloromethane at 0 ° C., 714 mg (2.90 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 520 mg (82% of theory) of the title compound.

Example 64

4- (4-chlorophenyl) -4- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

140 mg (0.38 mmol) of the compound from Example 43 were introduced into 22 mL of dichloromethane at 0 ° C., 185 mg (0.75 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was stirred at room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 122 mg (80% of theory) of the title compound.

Example 65

4- (4-chloro-2-methylphenyl) -4- {7-[(ethylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

73.0 mg (0.19 mmol) of the compound from Example 44 were introduced into 11 mL of dichloromethane at 0 ° C., 94.0 mg (0.38 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 38.0 mg (48% of theory) of the title compound. Obtained.

Example 66

4- (4-chloro-2-methylphenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

200 mg (0.54 mmol) of the compound from Example 45 were introduced into 30 mL of dichloromethane at 0 ° C., 267 mg (1.08 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol is added, the residue is concentrated and taken up in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and Concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 87 mg (40% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 4: 1; Flow rate: 20 ml / min; Temperature: RT; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added):

Enantiomer 66-1:

R _t = 6.92 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 3: 2; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm];

Enantiomer 66-2:

R _t = 7.52 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 3: 2; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm].

Example 67

4- (4-fluoro-2-methylphenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

50 mg (0.14 mmol) of the compound from Example 46 were introduced into 10 mL of dichloromethane at 0 ° C., 69.9 mg (0.28 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir for 4 hours and then at reflux for 15 minutes. 2 mL of methanol was added and the residue was concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution and the phases were separated. The organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 24.6 mg (45% of theory) of the title compound.

Example 68

4- [2-fluoro-4- (trifluoromethyl) phenyl] -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

100 mg (0.21 mmol) of the compound from Example 47 in 85% purity was introduced into 14 mL of dichloromethane at 0 ° C. and 118 mg (0.48 mmol) of 70% purity of meta-chloroperbenzoic acid was added, The mixture was stirred at rt overnight. The residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 65 mg (71% of theory) of the title compound.

Example 69

4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} -4- (naphthalen-2-yl) butanonitrile

50 mg (0.14 mmol) of the compound from Example 48 were introduced into 10 mL of dichloromethane at 0 ° C., 66.5 mg (0.27 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir for 4 hours and then at reflux for 15 minutes. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 30 mg (55% of theory) of the title compound.

Example 70

5- (4-chlorophenyl) -5- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} pentanonitrile

50 mg (0.14 mmol) of the compound from Example 49 were introduced into 9 mL of dichloromethane at 0 ° C., 66.8 mg (0.27 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight and then under reflux for 15 minutes. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 30 mg (55% of theory) of the title compound.

Example 71

4- (4-chlorophenyl) -4- {6-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

0.66 g (1.77 mmol) of the compound from Example 50 were introduced into 120 mL of dichloromethane at 0 ° C., 1.09 g (4.43 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 3 hours. 2 mL of methanol was added and the mixture was extracted with water and saturated aqueous sodium bicarbonate solution. The phases were separated, the combined organic phases were dried over sodium sulphate and filtered and the solvent was removed from the residue in vacuo. The crude product was first purified by preparative HPLC (mobile phase: acetonitrile / water gradient), then the resulting slightly impure product was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 3/2). 317 mg (44% of theory) of the title compound were obtained.

Example 72

4- {6-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

0.95 g (2.35 mmol) of the compound from Example 51 was introduced into 160 mL of dichloromethane at 0 ° C., 1.45 g (5.88 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 3 hours. 2 mL of methanol was added and the mixture was extracted with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The phases were separated and the solvent removed from the organic phase in vacuo. The crude product was first purified by preparative HPLC (mobile phase: acetonitrile / water gradient), and then the resulting slightly impure product was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1/1). 483 mg (47% of theory) of the title compound were obtained.

Example 73

4- (1-benzothiophen-5-yl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 72 starting from 284 mg (0.75 mmol) of the compound from Example 52. 409 mg (54% of theory) of the desired compound were obtained.

Example 74

4- (2-bromo-1,3-thiazol-5-yl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

125 mg (0.31 mmol) of the compound from Example 53 were introduced into 15 mL of dichloromethane at 0 ° C., 152 mg (0.62 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was first purified by preparative HPLC (mobile phase: acetonitrile / water gradient), and then the resulting slightly impure product was purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1/1). 119 mg (85% of theory) of the title compound were obtained.

Example 75

3-methyl-4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

335 mg (0.83 mmol) of the compound from Example 54 were introduced into 40 mL of dichloromethane at 0 ° C., 410 mg (1.67 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in a small amount of acetonitrile. The product-containing solid was filtered and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). The product-containing fractions were combined, taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, the solid was filtered off and the solvent removed to give 336 mg (93% of theory) of the title compound as a mixture of diastereomers.

Example 76

4- (4-chlorophenyl) -3-methyl-4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 74 starting from 160 mg (0.43 mmol) of the compound from Example 55. 160 mg (92% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 77

4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

25 mg (64 μmol) of the compound from Example 35 were introduced into 5 mL of dichloromethane at 0 ° C., 16 mg (64 μmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir overnight. The residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, 0.1% formic acid added) to give 24 mg (92% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 78

4- (4-chlorophenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 77 starting from 85.0 mg (0.24 mmol) of the compound from Example 36. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient, 0.1% formic acid added) gave 86 mg (97% of theory) of the title compound as a mixture of diastereomers.

Diastereomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 15 ml / min; Temperature: 30 ° C .; UV detection: 220 nm]:

Diastereomers 78-1:

R _t = 14.17 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1.0 ml / min; Temperature: 30 ° C .; UV detection: 220 nm];

Diastereomers 78-2:

R _t = 15.40 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1.0 ml / min; Temperature: 30 ° C .; UV detection: 220 nm];

Diastereomers 78-3:

R _t = 16.85 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1.0 ml / min; Temperature: 30 ° C .; UV detection: 220 nm];

Diastereomers 78-4:

R _t = 20.10 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1.0 ml / min; Temperature: 30 ° C .; UV detection: 220 nm].

Example 79

4- (4-chloro-2-fluorophenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

200 mg (0.54 mmol) of the compound from Example 38 were introduced into 30 mL of dichloromethane at 0 ° C., 132 mg (0.54 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and concentrated I was. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 107 mg (51% of theory) as a mixture of diastereomers. .

Example 80

4- (4-chloro-2-fluorophenyl) -4- {5-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

80.0 mg (0.21 mmol) of the compound from Example 40 were introduced into 5 mL of dichloromethane at 0 ° C., 53.0 mg (0.22 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 58.8 mg (71% of theory) of the title compound. Was obtained as a mixture of diastereomers.

Example 81

4- (2,4-dichlorophenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

200 mg (0.51 mmol) of the compound from Example 41 were introduced into 30 mL of dichloromethane at 0 ° C., 127 mg (0.51 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir overnight. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and concentrated I was. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 99 mg (48% of theory) of the title compound as a mixture of diastereomers. .

Example 82

4- (2,4-dichlorophenyl) -4- {5-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

100 mg (0.25 mmol) of the compound from Example 42 were introduced into 14 mL of dichloromethane at 0 ° C., 60.5 mg (0.25 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 80 mg (76% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 83

4- (4-chlorophenyl) -4- {5-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

64.0 mg (0.17 mmol) of the compound from Example 43 were introduced into 10 mL of dichloromethane at 0 ° C., 42.3 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was stirred at room temperature. Stir overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 54 mg (79% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 84

4- (4-chloro-2-methylphenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 79 starting from 200 mg (0.54 mmol) of the compound from Example 45. 146 mg (70% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 85

4- (4-fluoro-2-methylphenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

50 mg (0.14 mmol) of the compound from Example 46 were introduced into 10 mL of dichloromethane at room temperature, 35.0 mg (0.14 mmol) of 70% pure meta-chloroperbenzoic acid was added, and the mixture was added at 4 room temperature. Stir for hours. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 24.6 mg (47% of theory) as a mixture of diastereomers. .

Example 86

4- [2-fluoro-4- (trifluoromethyl) phenyl] -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

100 mg (0.21 mmol) of 85% purity of the compound from Example 47 were introduced into 14 mL of dichloromethane at 0 ° C., 59.1 mg (0.24 mmol) of 70% purity of meta-chloroperbenzoic acid was added, The mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 62 mg (71% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 87

5- (4-chlorophenyl) -5- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} pentanonitrile

50 mg (0.14 mmol) of the compound from Example 49 were introduced into 9 mL of dichloromethane while cooling on ice, 33.4 mg (0.14 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to stand at room temperature. Stir overnight at. 2 mL of methanol is added, the residue is concentrated and then dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated and the organic phase washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 33 mg (63% of theory) of the title compound as a mixture of diastereomers. .

Example 88

4- (4-chlorophenyl) -4- {6-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

300 mg (0.80 mmol) of the compound from Example 50 were introduced into 55 mL of dichloromethane at 0 ° C., 198 mg (0.80 mmol) of 70% pure meta-chloroperbenzoic acid was added, and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the mixture was extracted with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The phases were separated and the solvent removed from the organic phase in vacuo. The crude product was first purified by preparative HPLC (mobile phase: acetonitrile / water gradient), then the resulting slightly impure product was purified by flash chromatography on silica gel (mobile phase: ethyl acetate). 197 mg (63% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 89

4- {6-fluoro-7-[(methylsulfinyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 88 starting from 557 mg (1.37 mmol) of the compound from Example 51. 412 mg (71% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 90

4- (1-benzothiophen-5-yl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

157 mg (0.42 mmol) of the compound from Example 52 were introduced into 28 mL of dichloromethane at 0 ° C., 102 mg (0.42 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol and a small amount of ethyl acetate were added and the mixture was extracted with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The phases were separated and the solvent removed from the organic phase in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 141 mg (86% of theory) of the title compound as a mixture of diastereomers.

Example 91

3-methyl-4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] butanonitrile

150 mg (0.37 mmol) of the compound from Example 54 were introduced into 20 mL of dichloromethane at 0 ° C., 92 mg (0.37 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 150 mg (96% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 92

2- [1- (4-chlorophenyl) -1- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

150 mg (0.68 mmol) of the compound from Example 75A and 120 mg (0.68 mmol) of the compound from Example 8A were introduced into 4 mL of dichloromethane at 0 ° C. and 157 mg (0.71 mmol) of indium chloride ( III) was added and the mixture was stirred at RT for 1 h and at reflux for 0.5 h. After cooling, 0.05 ml (0.68 mmol) trifluoroacetic acid were added and the mixture was stirred at reflux for 5 minutes. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 117 mg (45% of theory) as a mixture of diastereomers. .

Example 93

3- (1-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfanyl) methyl] -1H-indole

200 mg (0.78 mmol) of 75% purity compound from Example 76A and 152 mg (0.86 mmol) of compound from Example 8A were introduced into 3.8 mL of dichloromethane at 0 ° C. and 0.07 ml (0.94 mmol) Trifluoroacetic acid was added and the mixture was stirred at 0 ° C for 4 h. It was diluted with dichloromethane, added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 175 mg (64% of theory) of the title compound.

Example 94

3- (1-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -5-fluoro-7-[(methylsulfanyl) methyl] -1H-indole

633 mg (2.47 mmol) of 75% purity compound from Example 76A and 530 mg (2.71 mmol) of compound from Example 11A were introduced into 12 mL of dichloromethane at 0 ° C. and 0.23 ml (2.96 mmol) Trifluoroacetic acid was added and the mixture was stirred at 0 ° C for 4 h. It was diluted with dichloromethane, added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 570 mg (63% of theory) of the title compound.

Example 95

3- [1-cyclopropyl-1- (4-fluorophenyl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

559 mg (3.10 mmol) of the compound from Example 77A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 12 mL of dichloromethane. The reaction mixture was stirred at rt for 30 min, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 361 mg (38% of theory) of the title compound.

Example 96

3- [1-cyclopropyl-1- (2,4-difluorophenyl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 95 starting from 500 mg (2.82 mmol) of the compound from Example 8 and 615 mg (3.10 mmol) of the compound from Example 78A. 227 mg (94% purity, 21% of theory) were obtained.

Example 97

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 95 starting from 3.00 g (16.92 mmol) of the compound from Example 8 and 4.00 g (18.62 mmol) of the compound from Example 79A. As a difference, the reaction mixture was stirred at 0 ° C. for 2 hours and then warmed to room temperature. 1.54 g (24% of theory) of the desired compound were obtained.

Example 98

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl] -5-fluoro-7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 95 starting from 500 mg (2.56 mmol) of the compound from Example 8 and 605 mg (2.82 mmol) of the compound from Example 79A. As a difference, the reaction mixture was stirred at 0 ° C. for 2 hours and then warmed to room temperature. 67 mg (7% of theory) of the desired compound were obtained.

Example 99

3-{(4-fluorophenyl) [4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfanyl) methyl] -1H-indole

503 mg (1.86 mmol) of the compound from Example 80A and 75 mg (0.34 mmol) of indium (III) chloride were added to 300 mg (1.69 mmol) of the compound from Example 8 in 15 mL of toluene. The reaction mixture was stirred at 80 ° C. for 5 hours, an additional 187 mg (0.85 mmol) of indium (III) chloride was added and the mixture was stirred for another 5 hours. After cooling to room temperature, the reaction solution was mixed with water and ethyl acetate and the solids were filtered off. The phases of the filtrate were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 107 mg (15% of theory) of the title compound.

Example 100

3-[(4-chlorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

2.94 g (12.41 mmol) of the compound from Example 81A and 2.50 g (11.28 mmol) of indium (III) chloride were added to 2.00 g (11.28 mmol) of the compound from Example 8 in 100 mL of toluene. The reaction mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, the reaction solution was mixed with water and ethyl acetate and the solids were filtered off. The phases of the filtrate were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 0.83 g (19% of theory) of the title compound.

Example 101

3-[(4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

509 mg (2.17 mmol) of the compound from Example 82A and 437 mg (1.97 mmol) of indium (III) chloride were added to 350 mg (1.97 mmol) of the compound from Example 8 in 15 mL of toluene. The reaction mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, the reaction solution was mixed with water and ethyl acetate and the solids were filtered off. The phases of the filtrate were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 174 mg (22% of theory) of the title compound.

Example 102

3-[(4-chloro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 101 starting from 380 mg (2.14 mmol) of the compound from Example 8 and 591 mg (2.36 mmol) of the compound from Example 83A. 307 mg (35% of theory) of the target compound were obtained.

Example 103

3-[(2,4-difluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 101 starting from 350 mg (1.97 mmol) of the compound from Example 8 and 470 mg (1.97 mmol) of the compound from Example 84A. 191 mg (24% of theory) of the desired compound were obtained.

Example 104

3-[(4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 101 starting from 1.50 g (8.46 mmol) of the compound from Example 8 and 2.15 g (8.46 mmol) of the compound from Example 85A. However, the difference is the stirring at 80 ° C. for 3 hours. 0.66 g (19% of theory) of the desired compound were obtained.

Example 105

3-[(4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 101 starting from 500 mg (2.56 mmol) of the compound from Example 9 and 652 mg (2.56 mmol) of the compound from Example 85A. 197 mg (18% of theory) of the desired compound were obtained.

Example 106

2- [1- (4-chlorophenyl) -1- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

112 mg (0.29 mmol) of the compound from Example 92 were introduced into 20 mL of dichloromethane at 0 ° C., 145 mg (0.59 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to 62 mg (51% of theory) of the title compound. Was obtained as a mixture of diastereomers.

Example 107

3- (1-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfonyl) methyl] -1H-indole

240 mg (0.68 mmol) of the compound from Example 93 were introduced into 40 mL of dichloromethane at 0 ° C., 354 mg (1.43 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid), 92 mg (35% of theory) The title compound was obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 4: 1; Flow rate: 20 ml / min; Temperature: RT; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added):

Enantiomer 107-1:

R _t = 4.63 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 3: 2; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm];

Yield: 28.7 mg

Enantiomer 107-2:

R _t = 4.95 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 3: 2; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm];

Yield: 25.0 mg

Example 108

3- (1-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

80.0 mg (0.22 mmol) of the compound from Example 94 were introduced into 6 mL of dichloromethane at 0 ° C., 109 mg (0.44 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 36.1 mg (42% of theory) of the title compound. Obtained.

Example 109

3- [1-cyclopropyl-1- (4-fluorophenyl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

107 mg (0.31 mmol) of the compound from Example 95 were introduced into 21 mL of dichloromethane at 0 ° C., 155 mg (0.63 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was dissolved in acetonitrile and purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 106 mg (91% of theory) of the title compound were obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 7: 3; Flow rate: 25 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 109-1:

R _t = 4.42 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 25.8 mg

Enantiomer 109-2:

R _t = 4.96 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 23.7 mg

Example 110

3- [1-cyclopropyl-1- (2,4-difluorophenyl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 109 starting from 91 mg (0.26 mmol) of the compound from Example 96. 71 mg (72% of theory) of the desired compound were obtained.

Example 111

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl] -7-[(methylsulfonyl) methyl] -1H-indole

1.42 g (3.80 mmol) of the compound from Example 97 were introduced into 260 mL of dichloromethane at 0 ° C., 1.87 g (7.60 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 10 mL of methanol was added and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 1.23 g (80% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 7: 3; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 260 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 111-1:

R _t = 5.42 min [Column: Daicel Chiralpak IA, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 540.4 mg

Enantiomers 111-2:

R _t = 5.90 min [Column: Daicel Chiralpak IA, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 534.7 mg

Example 112

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 111 starting from 58 mg (0.15 mmol) of the compound from Example 98. 57 mg (86% of theory) of the desired compound were obtained.

Example 113

3-{(4-fluorophenyl) [4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfonyl) methyl] -1H-indole

52 mg (0.12 mmol) of the compound from Example 99 were introduced into 12 mL of dichloromethane at 0 ° C., 60 mg (0.24 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 38 mg (68% of theory) of the title compound were obtained.

Example 114

3-[(4-chlorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

0.83 g (2.10 mmol) of the compound from Example 100 were introduced into 150 mL of dichloromethane at 0 ° C., 1.03 g (4.19 mmol) of 70% purity of meta-chloroperbenzoic acid was added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 0.70 g (78% of theory) were obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / ethanol 7: 3; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 114-1:

R _t = 12.89 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 7: 3; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 217.0 mg

Enantiomer 114-2:

R _t = 13.91 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 7: 3; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 186.0 mg

Example 115

3-[(4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

65 mg (0.17 mmol) of the compound from Example 101 were introduced into 8 mL of dichloromethane at 0 ° C., 81 mg (0.33 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 63 mg (88% of theory) of the title compound were obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Eluent: isohexane / ethanol 6: 4; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 115-1:

R _t = 5.09 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 5: 5; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 15 mg

Enantiomer 115-2:

R _t = 5.62 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 5: 5; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 15 mg

Example 116

3-[(4-chloro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

130 mg (0.32 mmol) of the compound from Example 102 were introduced into 15 mL of dichloromethane at 0 ° C., 156 mg (0.63 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 106 mg (76% of theory) of the title compound were obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Eluent: isohexane / ethanol 6: 4; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 116-1:

R _t = 5.38 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 5: 5; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 48.0 mg

Enantiomer 116-2:

R _t = 6.15 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 5: 5; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 39.0 mg

Example 117

3-[(2,4-difluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

75 mg (0.19 mmol) of the compound from Example 103 were introduced into 14 mL of dichloromethane at 0 ° C., 93 mg (0.34 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 49 mg (60% of theory) of the title compound were obtained.

Example 118

3-[(4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

335 mg (0.81 mmol) of the compound from Example 104 were introduced into 25 mL of dichloromethane at 0 ° C., 93 mg (0.34 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in acetonitrile, the remaining solid was filtered off and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 286 mg (79% of theory) of the title compound were obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / ethanol 6: 4; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 118-1:

R _t = 6.20 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 5: 5; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Enantiomer 118-2:

R _t = 6.96 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 5: 5; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm].

Example 119

3-[(4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

110 mg (0.26 mmol) of the compound from Example 105 were introduced into 12 mL of dichloromethane at 0 ° C., 126 mg (0.51 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 96 mg (81% of theory) of the title compound were obtained.

Example 120

3- (1-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfinyl) methyl] -1H-indole

62.0 mg (0.18 mmol) of the compound from Example 93 were introduced into 10 mL of dichloromethane at 0 ° C., 43.5 mg (0.18 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir overnight. 2 mL of methanol was added and the residue was concentrated, then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid), 48 mg (74% of theory) The title compound of was obtained as a mixture of diastereomers.

Example 121

3- (1-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -5-fluoro-7-[(methylsulfinyl) methyl] -1H-indole

80.0 mg (0.22 mmol) of the compound from Example 94 were introduced into 6 mL of dichloromethane at 0 ° C., 56.1 mg (0.23 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir overnight. Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 43.6 mg (52% of theory) of the title compound. Was obtained as a mixture of diastereomers.

Example 122

3- [1-cyclopropyl-1- (4-fluorophenyl) ethyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 91 starting from 273 mg (0.81 mmol) of the compound from Example 95. 213 mg (73% of theory) of the desired compound were obtained as a mixture of diastereomers.

Diastereomers and enantiomers were separated by preparative HPLC on chiral [first column: Daicel chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 93: 7; Flow rate: 25 ml / min; Temperature: 24 ° C .; UV detection: 230 nm1. Second column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: Milli-Q water / ethanol 93: 7; Flow rate: 25 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Isomer 122-1:

R _t = 9.84 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 9: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 260 nm];

Isomer 122-2:

R _t = 8.31 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 9: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 260 nm].

Isomer 122-3:

R _t = 8.86 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 9: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 260 nm].

Isomer 122-4:

R _t = 10.30 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 9: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 260 nm].

Example 123

3- [1-cyclopropyl-1- (2,4-difluorophenyl) ethyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared similar to the synthesis of the compound from Example 91 starting from 217 mg (94% purity, 0.61 mmol) of the compound from Example 96. 212 mg (99% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 124

3- [1- (4-chloro-2-fluorophenyl) -1-cyclopropylethyl] -7-[(methylsulfinyl) methyl] -1H-indole

100 mg (0.27 mmol) of the compound from Example 97 were introduced into 18 mL of dichloromethane at 0 ° C., 66 mg (0.27 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solvent was removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 86 mg (83% of theory) of the title compound as a mixture of diastereomers.

Example 125

3-{(4-fluorophenyl) [4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfinyl) methyl] -1H-indole

75 mg (0.18 mmol) of the compound from Example 99 were introduced into 25 mL of dichloromethane at 0 ° C., 43 mg (0.18 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified twice by preparative HPLC (mobile phase: acetonitrile / water gradient). 65 mg (84% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 126

3-[(4-chlorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

110 mg (0.28 mmol) of the compound from Example 100 were introduced into 20 mL of dichloromethane at 0 ° C., 68 mg (0.28 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 93 mg (81% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 127

3-[(4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

65 mg (0.17 mmol) of the compound from Example 101 were introduced into 8 mL of dichloromethane at 0 ° C., 41 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 67 mg (99% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 128

3-[(4-chloro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

130 mg (0.32 mmol) of the compound from Example 102 were introduced into 15 mL of dichloromethane at 0 ° C., 78 mg (0.32 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 129 mg (96% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 129

3-[(2,4-difluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

75 mg (0.19 mmol) of the compound from Example 103 were introduced into 14 mL of dichloromethane at 0 ° C., 47 mg (0.19 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 74 mg (95% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 130

3-[(4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

70 mg (0.17 mmol) of the compound from Example 104 were introduced into 10 mL of dichloromethane at 0 ° C., 42 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 76 mg (99% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 131

3-[(4-chloro-2-fluorophenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfinyl) methyl] -1H-indole

50 mg (0.12 mmol) of the compound from Example 105 were introduced into 6 mL of dichloromethane at 0 ° C., 29 mg (0.12 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 45 mg (87% of theory) of the title compound were obtained as a mixture of diastereomers.

Example 132

3- (4-chloro-2-methylphenyl) -3- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 690 mg (1.64 mmol) of the compound from Example 98A in 10 mL of THF was added dropwise to 5.8 ml (5.75 mmol) of a 1N lithium aluminum hydride solution in THF in 20 mL of THF at room temperature under argon. 1N hydrochloric acid was then added, the mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 0.60 g (97% of theory) of the title compound.

Example 133

3- [2-chloro-4- (trifluoromethyl) phenyl] -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 1.30 g (2.85 mmol) of the compound from Example 99A in 20 mL of THF was added dropwise to 10 ml (9.98 mmol) of a 1N lithium aluminum hydride solution in THF in 80 mL of THF at room temperature under argon. 1N hydrochloric acid was then added, the mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 0.73 g (61% of theory) of the title compound.

Example 134

3- (4-methylphenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 2.41 g (6.57 mmol) of the compound from Example 100A in 20 mL of THF was added dropwise to 23 ml (23.0 mmol) of a 1N lithium aluminum hydride solution in THF in 80 mL of THF at room temperature under argon. 1N hydrochloric acid was then added, the mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 1.77 g (83% of theory) of the title compound.

Example 135

3- (4-chloro-3-fluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 1.74 g (4.28 mmol) of the compound from Example 101A in 7 mL of tetrahydrofuran was diluted with 15.0 ml (15.05 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 20 mL of tetrahydrofuran under argon at room temperature. Was added drop wise. The mixture was stirred at 60 ° C. for 1 h, then water and acetonitrile were added and the suspension was filtered through diatomaceous earth. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 1.36 g (87% of theory) of the title compound were obtained.

Example 136

3- (4-chloro-2,6-difluorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

9.0 ml (9.0 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 12 mL of tetrahydrofuran under argon at room temperature in a solution of 1.09 g (2.56 mmol) of compound from Example 102A in 6 mL tetrahydrofuran. Was added drop wise. The mixture was stirred at 60 ° C. for 1 h, then water and acetonitrile were added and the suspension was filtered through diatomaceous earth. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 0.88 g (90% of theory) of the title compound were obtained.

Example 137

3- (2,2-difluoro-1,3-benzodioxol-5-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propane-1- Come

A solution of 1.67 g (3.86 mmol) of the compound from Example 103A in 8 mL tetrahydrofuran was dissolved in 3.5 mL (13.5 mmol) 1N solution of lithium aluminum hydride in tetrahydrofuran in 16 mL tetrahydrofuran under argon at room temperature. Was added drop wise. The mixture was stirred at 60 ° C. for 1 h, then water and acetonitrile were added and the suspension was filtered through diatomaceous earth. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 1.39 g (92% of theory) of the title compound were obtained.

Example 138

3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -3- [4- (trifluoromethyl) phenyl] butan-1-ol

1.59 g (91% purity, approximately 6.77 mmol) of the compound from Example 89A and 1.50 g (6.77 mmol) of indium (III) chloride from 1.20 g (6.77 mmol) of Example 8A in 29 mL of toluene Was added. The reaction mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, the reaction solution was mixed with water and ethyl acetate and the solids were filtered off. The phases of the filtrate were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 0.14 g (5% of theory) of the title compound.

Example 139

3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butan-1-ol

A solution of 740 mg (1.84 mmol) of the compound from Example 104A in 20 mL of tetrahydrofuran was dissolved in 5.5 mL (5.5 mL) of a 1N solution of diisobutylaluminum hydride in dichloromethane in 20 mL of tetrahydrofuran under argon at room temperature. mmol). The mixture was stirred at rt for 2 h, then water and dichloromethane were added and the phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 437 mg (66% of theory) of the title compound were obtained.

Example 140

3- (4-chlorophenyl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} pentan-1-ol

Synthesis of Examples 88A and 89A starting from 3.04 g (14.10 mmol) of 3- (4-chlorophenyl) pentane-1,3-diol (1- (4-chlorophenyl) propan-1-one and ethyl acetate Similarly prepared) and 3.12 g (14.10 mmol) of indium (III) chloride were added to 2.50 g (14.10 mmol) of the compound from Example 8A in 60 mL of toluene. The reaction mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, the reaction solution was mixed with water and ethyl acetate and the solid was filtered through diatomaceous earth. The phases of the filtrate were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to afford 2.13 g (40% of theory) of the title compound.

Example 141

3- (4-chlorophenyl) -3-cyclopropyl-3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} propan-1-ol

A solution of 62 mg (0.15 mmol) of the compound from Example 105A in 0.5 mL tetrahydrofuran 0.51 ml (0.51 mmol) 1N solution of lithium aluminum hydride in tetrahydrofuran in 1 mL tetrahydrofuran under argon at room temperature Was added drop wise. The mixture was stirred at 60 ° C. for 1 h, then mixed with water and acetonitrile and the suspension was filtered through diatomaceous earth. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 52 mg (93% of theory) of the title compound were obtained.

Example 142

3- (2,3-dihydro-1,4-benzodioxin-6-yl) -3- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butan-1-ol

5.14 ml (5.14 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 6 mL of tetrahydrofuran under argon at room temperature with a solution of 625 mg (1.47 mmol) of the compound from Example 106A in 3 mL tetrahydrofuran. Dropped in The mixture was stirred at 60 ° C. for 1 h, then mixed with water and acetonitrile and the suspension was filtered through diatomaceous earth. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 491 mg (87% of theory) of the title compound were obtained.

Example 143

3- (4-chlorophenyl) -3- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} pentan-1-ol

60 mg (0.16 mmol) of the compound from Example 140 were introduced into 6 mL of dichloromethane at 0 ° C., 40 mg (0.16 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 62 mg (99% of theory) of the title compound as a mixture of diastereomers.

Example 144

3- (4-chloro-2-fluorophenyl) -3- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

33.2 mg (0.12 mmol) of 60% pure meta-chloroperbenzoic acid were added to 40.0 mg (0.11 mmol) of the compound from Example 4 in 5 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 16.2 mg (37% of theory) of the title compound.

Example 145

3- (4-chloro-2-methylphenyl) -3- {7-[(ethylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

106 mg (0.43 mmol) of 70% pure meta-chloroperbenzoic acid were added to 80.0 mg (0.21 mmol) of the compound from Example 10 in 12 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 45 mg (51% of theory) of the title compound.

Example 146

3- (2,2-difluoro-1,3-benzodioxol-5-yl) -3- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propane-1- Come

140 mg (0.36 mmol) of the compound from Example 137 were introduced into 24 mL of dichloromethane at 0 ° C., 176 mg (0.72 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 43 mg (28% of theory) of the title compound.

Example 147

3- (4-chlorophenyl) -3- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} pentan-1-ol

2.12 g (5.67 mmol) of the compound from Example 140 were introduced into 150 mL of dichloromethane at 0 ° C., 2.80 g (11.34 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 15 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 1.76 g (77% of theory) of the title compound.

Example 148

3- (4-chloro-2-methylphenyl) -3- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} propan-1-ol

53.5 mg (0.22 mmol) of 70% purity meta-chloroperbenzoic acid was added to 40.0 mg (0.11 mmol) of the compound from Example 132 in 3 mL of dichloromethane at 0 ° C. and the mixture was stirred at rt overnight. . 2 mL of methanol was added and the residue was concentrated, then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid), 24.0 mg (55% of theory) The title compound was obtained.

Example 149

4- (4-chloro-2-methylphenyl) -4- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

174 mg (2.67 mmol) potassium cyanide and 8.1 mg (0.07 mmol) 4-N, N-dimethylaminopyridine were added to 608 mg (1.33 mmol) of the compound from Example 107A in 30 mL of DMSO. The mixture was stirred at 120 ° C. for 2 hours, then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 154 mg (30% of theory) of the title compound.

Example 150

4- [2-chloro-4- (trifluoromethyl) phenyl] -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

176 mg (2.70 mmol) of potassium cyanide and 8.2 mg (0.07 mmol) of 4-N, N-dimethylaminopyridine were added to 664 mg (1.35 mmol) of the compound from Example 108A in 29 mL of DMSO. The mixture was stirred at 120 ° C. for 1 hour, then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 460 mg (81% of theory) of the title compound.

Example 151

4- (4-methylphenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

671 mg (10.3 mmol) of potassium cyanide and 31.5 mg (0.26 mmol) of 4-N, N-dimethylaminopyridine were added to 2.08 g (5.15 mmol) of the compound from Example 109A in 112 mL of DMSO. The mixture was stirred at 120 ° C. for 1 hour, then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to afford 1.92 g (99% of theory) of the title compound.

Example 152

4- (4-chloro-3-fluorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

0.38 g (5.90 mmol) of potassium cyanide was added to 1.30 g (2.95 mmol) of the compound from Example 110A in 27 mL of DMSO. The mixture was stirred at 80 ° C. for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The solvent was removed from the combined organic phases and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 0.95 g (86% of theory) of the desired compound were obtained.

Example 153

4- (4-chloro-2,6-difluorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

0.30 g (4.57 mmol) potassium cyanide was added to 1.05 g (2.28 mmol) of compound from Example 111A in 21 mL of DMSO. The mixture was stirred at 80 ° C. for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The solvent was removed from the combined organic phases and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 0.74 g (83% of theory) of the desired compound were obtained.

Example 154

4- (2,2-difluoro-1,3-benzodioxol-5-yl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

0.37 g (5.76 mmol) of potassium cyanide was added to 1.35 g (2.88 mmol) of the compound from Example 112A in 26 mL of DMSO. The mixture was stirred at 80 ° C. for 3 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The solvent was removed from the combined organic phases and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 0.90 g (78% of theory) of the target compound were obtained.

Example 155

4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] pentanonitrile

33 mg (0.50 mmol) of potassium cyanide were added to 118 mg (0.25 mmol) of the compound from Example 113A in 1.5 mL of DMSO. The mixture was stirred at 80 ° C. for 4 h, water and dichloromethane were added to the reaction solution and the phases were separated. The organic phase was extracted with dichloromethane and the solvent was removed from the combined organic phases. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 62 mg (62% of theory) of the target compound were obtained.

Example 156

4- (4-chlorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} pentanonitrile

128 mg (1.96 mmol) of potassium cyanide were added to 430 mg (0.98 mmol) of the compound from Example 114A in 8 mL of DMSO. The mixture was stirred at 80 ° C. for 8 hours, water and dichloromethane were added to the reaction solution and the phases were separated. The organic phase was extracted with dichloromethane and the solvent was removed from the combined organic phases. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 280 mg (77% of theory) of the desired compound were obtained.

Example 157

4- (4-chlorophenyl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} hexanonnitrile

223 mg (3.43 mmol) of potassium cyanide were added to 775 mg (1.71 mmol) of the compound from Example 115A in 12 mL of DMSO. The mixture was stirred at 80 ° C. for 12 h, water and dichloromethane were added to the reaction solution and the phases were separated. The organic phase was extracted with dichloromethane and the solvent was removed from the combined organic phases. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 551 mg (84% of theory) of the target compound were obtained.

Example 158

4- (4-chlorophenyl) -4-cyclopropyl-4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} butanonitrile

16 mg (0.25 mmol) of potassium cyanide were added to 57 mg (0.12 mmol) of the compound from Example 116A in 1 mL of DMSO. The mixture was stirred at 80 ° C. for 16 h, water was added to the reaction solution and the crude product was purified directly by preparative HPLC (mobile phase: acetonitrile / water gradient). 29 mg (60% of theory) of the desired compound were obtained.

Example 159

4- (2,3-dihydro-1,4-benzodioxin-6-yl) -4- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} pentanonitrile

150 mg (2.30 mmol) potassium cyanide was added to 530 mg (1.15 mmol) of the compound from Example 117A in 10 mL of DMSO. The mixture was stirred at 80 ° C. for 16 hours, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The solvent was removed from the combined organic phases and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 328 mg (73% of theory) of the desired compound were obtained.

Example 160

4- (4-chloro-3-fluorophenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

300 mg (0.81 mmol) of the compound from Example 152 were introduced into 55 mL of dichloromethane at 0 ° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 266 mg (85% of theory) of the title compound as a mixture of diastereomers.

Example 161

4- (4-chloro-2,6-difluorophenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

231 mg (0.59 mmol) of the compound from Example 153 were introduced into 40 mL of dichloromethane at 0 ° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid was added, and the mixture was 0 ° C. Stirred for 2 h. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 171 mg (71% of theory) of the title compound as a mixture of diastereomers.

Example 162

4- (2,2-difluoro-1,3-benzodioxol-5-yl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} butanonitrile

272 mg (0.68 mmol) of the compound from Example 154 were introduced into 46 mL of dichloromethane at 0 ° C., 167 mg (0.68 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 236 mg (81% of theory) of the title compound as a mixture of diastereomers.

Example 163

4- (4-chlorophenyl) -4- {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} hexanonnitrile

120 mg (0.31 mmol) of the compound from Example 157 were introduced into 12 mL of dichloromethane at 0 ° C., 77 mg (0.31 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to afford 120 mg (96% of theory) of the title compound as a mixture of diastereomers.

Example 164

4- (4-chloro-2-methylphenyl) -4- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

87.5 mg (0.36 mmol) of 70% purity meta-chloroperbenzoic acid was added to 67.0 mg (0.17 mmol) of the compound from Example 149 in 5 mL of dichloromethane at 0 ° C. and the mixture was stirred at rt overnight. . Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 36.6 mg (51% of theory) of the title compound. Obtained.

Example 165

4- [2-chloro-4- (trifluoromethyl) phenyl] -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

406 mg (1.65 mmol) of 70% purity meta-chloroperbenzoic acid were added to 348 mg (0.82 mmol) of the compound from Example 150 in 6 mL of dichloromethane at 0 ° C. and the mixture was stirred at rt overnight. . It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added), 200 mg (53% of theory) of the title compound were obtained.

Example 166

4- (4-methylphenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

251 mg (1.02 mmol) of 70% purity meta-chloroperbenzoic acid were added to 200 mg (0.60 mmol) of the compound from Example 151 in 10 mL of dichloromethane and the mixture was stirred at rt overnight. 2 mL of methanol was added and the residue was concentrated and then taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 48.0 mg (22% of theory) of the title compound.

Example 167

4- (4-chloro-3-fluorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

300 mg (0.81 mmol) of the compound from Example 152 were introduced into 55 mL of dichloromethane at 0 ° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 266 mg (85% of theory) of the title compound.

Example 168

4- (4-chloro-2,6-difluorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

461 mg (1.18 mmol) of the compound from Example 153 are introduced into 80 mL of dichloromethane at 0 ° C., 581 mg (2.36 mmol) of 70% pure meta-chloroperbenzoic acid are added and the mixture is brought to 0 ° C. Stirred for 2 h. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 342 mg (68% of theory) of the title compound.

Example 169

4- (2,2-difluoro-1,3-benzodioxol-5-yl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

544 mg (1.36 mmol) of the compound from Example 154 were introduced into 93 mL of dichloromethane at 0 ° C., 670 mg (2.72 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was allowed to stand at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 352 mg (60% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 169-1:

R _t = 5.86 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Enantiomer 169-2:

R _t = 6.85 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm].

Example 170

4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} -4- [4- (trifluoromethyl) phenyl] pentanonitrile

45 mg (0.11 mmol) of the compound from Example 155 were introduced into 5 mL of dichloromethane at 0 ° C., 55 mg (0.22 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 43 mg (89% of theory) of the title compound.

Example 171

4- (4-chlorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} pentanonitrile

180 mg (0.49 mmol) of the compound from Example 156 were introduced into 20 mL of dichloromethane at 0 ° C., 241 mg (0.98 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 185 mg (95% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: selector poly- (on chiral silica gel based on N-methacryloyl-L-leucine dicyclopropylmethylamide), 5 μm, 250 mm x 20 mm; Eluent: isohexane / ethyl acetate 4: 6; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 260 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 171-1:

R _t = 4.06 min [Column: Selector Poly- (on Chiral Silicagel Based on N-Methacryloyl-L-Leucine Dicyclopropylmethylamide), 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethyl acetate 3: 7; Flow rate: 1.5 ml / min; Temperature: 24 ° C .; UV detection: 260 nm];

Yield: 54.0 mg

Enantiomer 171-2:

R _t = 4.83 min [Column: Selector Poly- (on Chiral Silicagel Based on N-Methacryloyl-L-Leucine Dicyclopropylmethylamide), 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethyl acetate 3: 7; Flow rate: 1.5 ml / min; Temperature: 24 ° C .; UV detection: 260 nm];

Yield: 55.0 mg

Example 172

4- (4-chlorophenyl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} hexanonnitrile

380 mg (0.99 mmol) of the compound from Example 157 were introduced into 40 mL of dichloromethane at 0 ° C., 489 mg (1.99 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 377 mg (92% of theory) of the title compound.

Enantiomers were separated by preparative HPLC on chiral [column: selector poly- (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 5 μm, 250 mm × 20 mm; Eluent: isohexane / ethyl acetate 4: 6; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 260 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 172-1:

R _t = 3.70 min [column: selector poly- (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethyl acetate 3: 7; Flow rate: 1.5 ml / min; Temperature: 24 ° C .; UV detection: 260 nm];

Yield: 102 mg

Enantiomer 172-2:

R _t = 4.86 min [column: selector poly- (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethyl acetate 3: 7; Flow rate: 1.5 ml / min; Temperature: 24 ° C .; UV detection: 260 nm];

Yield: 95 mg

Example 173

4- (4-chlorophenyl) -4-cyclopropyl-4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} butanonitrile

23 mg (0.06 mmol) of the compound from Example 158 were introduced into 4 mL of dichloromethane at 0 ° C., 29 mg (0.12 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was brought to 0 ° C. Stirred for 2 h. 1 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 21 mg (82% of theory) of the title compound.

Example 174

4- (2,3-dihydro-1,4-benzodioxin-6-yl) -4- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} pentanonitrile

185 mg (0.47 mmol) of the compound from Example 159 were introduced into 32 mL of dichloromethane at 0 ° C., 232 mg (0.94 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 128 mg (64% of theory) of the title compound.

Example 175

3- (5-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfanyl) methyl] -1H-indole

0.03 ml (0.40 mmol) trifluoroacetic acid is added to 00.0 ° C. in 7 mL mg (0.34 mmol) of the compound from Example 118A and 1.6 5.4 mg (0.37 mmol) of the compound from Example 8A in 1.6 mL of dichloromethane. And the mixture was stirred at 0 ° C for 4 h. It was diluted with dichloromethane, added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 48.8 mg (40% of theory) of the title compound.

Example 176

3- (6-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfanyl) methyl] -1H-indole

0.03 ml (0.40 mmol) of trifluoroacetic acid is added to 00.0 ° C. in 70.0 mg (0.34 mmol) of the compound from Example 119A and 1.6. 4 (0.37 mmol) of the compound from Example 8A in 1.6 mL of dichloromethane. And the mixture was stirred at 0 ° C for 4 h. It was diluted with dichloromethane, added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 52.4 mg (42% of theory) of the title compound.

Example 177

2- (1- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} -1- [4- (trifluoromethyl) phenyl] ethyl) cyclopropanecarbonitrile [trans-diastere Isomer mixture]

0.02 ml (0.24 mmol) of trifluoroacetic acid and 43.3 mg (0.20 mmol) of indium (III) chloride were added to 59.5 mg (0.20 mmol) of compound from Example 132A and 69.5 mg (in 2 mL of dichloromethane at room temperature). 0.39 mmol) to the compound from Example 8A and the mixture was heated at reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 9.0 mg (11% of theory) of the diastereomer. Obtained as a mixture.

Example 178

2- [1- (2,4-difluorophenyl) -1- {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

0.08 ml (1.08 mmol) trifluoroacetic acid and 218 mg (0.99 mmol) of indium (III) chloride were 200 mg (0.90 mmol) of compound from Example 133A and 318 mg (8 mL in 8 mL of dichloromethane at room temperature). 1.79 mmol) to the compound from Example 8A and the mixture was heated at reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 128 mg (37% of theory) of the diastereomer. Obtained as a mixture.

Example 179

2- [1- (4-chlorophenyl) -1- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [trans-diastere Isomer mixture]

367 mg (1.66 mmol) of indium (III) chloride and 0.12 ml (1.58 mmol) of trifluoroacetic acid were added 350 mg (1.58 mmol) of the compound from Example 75A and 308 mg in 9 mL of dichloromethane at room temperature. 1.58 mmol) to the compound from Example 11A and the mixture was heated to reflux for 15 minutes. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 32.5 mg (5% of theory) as a mixture of diastereomers. .

Example 180

3- [1- (4-chlorophenyl) -1- (2,2-difluorocyclopropyl) ethyl] -7-[(methylsulfanyl) methyl] -2,3-dihydro-1H-indole

76.2 mg (0.43 mmol) of the compound from Example 8A dissolved in 1 mL of toluene was added to 190 mg (0.86 mmol) of indium (III) chloride and 100 mg (0.43 mmol) in 1 mL of toluene at room temperature. To the compound from 134A was added and the mixture was stirred at 80 ° C for 2 h. Then 1.90 g (8.60 mmol) of indium (III) chloride were added and the mixture was stirred at 80 ° C. for 1 hour. It was diluted with toluene, washed with water and the organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 16.0 mg (10% of theory) as a mixture of diastereomers. .

Example 181

3- (1-ethyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfanyl) methyl] -1H-indole

515 mg (2.33 mmol) of indium (III) chloride and 0.17 ml (2.22 mmol) of trifluoroacetic acid at 400 ° C. (2.22 mmol) of compound from Example 135A and 393 mg in 12 mL of dichloromethane at 0 ° C. (2.22 mmol) was added to the compound from Example 8A and the mixture was stirred at rt for 1 h. It was diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 33 mg (4% of theory) as the mixture of diastereomers. .

Example 182

3- {1-cyclopropyl-1- [2-fluoro-4- (trifluoromethyl) phenyl] ethyl} -7-[(methylsulfanyl) methyl] -1H-indole

0.02 ml (0.24 mmol) trifluoroacetic acid is added to 50.0 mg (0.20 mmol) of the compound from Example 136A and 35.7 mg (0.20 mmol) of the compound from Example 8A in 4 mL of dichloromethane, and the mixture Was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 10.0 mg (12% of theory) of the diastereomer. Obtained as a mixture.

Example 183

3- [1-cyclopropyl-1- (4-methylphenyl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

0.23 ml (3.00 mmol) of trifluoroacetic acid is added to 885 mg (4.99 mmol) of the compound from Example 8A and 440 mg (2.50 mmol) of the compound from Example 137A in 44 mL of dichloromethane and the mixture Was stirred at rt overnight. The reaction mixture was concentrated on a rotary evaporator. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 87.4 mg (10% of theory) as a mixture of diastereomers. .

Example 184

3- [1- (4-chlorophenyl) -1-cyclopropylethyl] -7-[(methylsulfanyl) methyl] -1H-indole

600 mg (3.05 mmol) of the compound from Example 138A and 0.28 ml (3.66 mmol) of trifluoroacetic acid were added to 541 mg (3.05 mmol) of the compound from Example 8A in 4 mL of dichloromethane. The reaction mixture was stirred for 30 minutes at room temperature, then the crude product was subjected to three times by preparative HPLC (mobile phase: acetonitrile / water gradient) and to flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10/1). Purification by 1 time. 441 mg (41% of theory) of the title compound were obtained.

Example 185

3- {1-cyclopropyl-1- [4- (trifluoromethyl) phenyl] ethyl} -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 184 starting from 462 mg (2.61 mmol) of the compound from Example 8A and 600 mg (2.61 mmol) of the compound from Example 139A. 273 mg (27% of theory) of the desired compound were obtained.

Example 186

3- [1-cyclopropyl-1- (3-fluoro-4-methoxyphenyl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

100 mg (0.48 mmol) of the compound from Example 140A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 84 mg (0.48 mmol) of the compound from Example 8A in 2.5 mL of dichloromethane. The reaction mixture was stirred at rt for 30 min, then the crude product was purified directly by preparative HPLC (mobile phase: acetonitrile / water gradient). 63 mg (361% of theory) of the title compound were obtained.

Example 187

3- [1- (1-benzothiophen-5-yl) -1-cyclopropylethyl] -7-[(methylsulfanyl) methyl] -1H-indole

600 mg (2.75 mmol) of the compound from Example 141A and 0.25 ml (3.30 mmol) of trifluoroacetic acid were added to 487 mg (2.75 mmol) of the compound from Example 8A in 4 mL of dichloromethane. The reaction mixture was stirred at rt for 30 min, then the crude product was subjected to two times by preparative HPLC (mobile phase: acetonitrile / water gradient) and to flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10/1). Purification by 1 time. 404 mg (39% of theory) of the title compound were obtained.

Example 188

3- [1-cyclopropyl-1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

400 mg (1.82 mmol) of the compound from Example 142A and 0.17 ml (2.18 mmol) of trifluoroacetic acid were added to 322 mg (1.82 mmol) of the compound from Example 8A in 3 mL of dichloromethane. The reaction mixture was stirred at rt for 30 min, then the crude product was purified twice by preparative HPLC (mobile phase: acetonitrile / water gradient) and by recrystallization from acetonitrile. 184 mg (27% of theory) of the title compound were obtained.

Example 189

3- [1- (1,3-benzodioxol-5-yl) -1-cyclopropylethyl] -7-[(methylsulfanyl) methyl] -1H-indole

600 mg (2.91 mmol) of the compound from Example 143A and 0.27 ml (3.49 mmol) of trifluoroacetic acid were added to 516 mg (2.91 mmol) of the compound from Example 8A in 4 mL of dichloromethane. The reaction mixture was stirred at rt for 30 min, then the crude product was purified twice by preparative HPLC (mobile phase: acetonitrile / water gradient). 377 mg (35% of theory) of the title compound were obtained.

Example 190

3- [1-cyclopropyl-1- (2,2-difluoro-1,3-benzodioxol-5-yl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 186 starting from 32 mg (0.18 mmol) of the compound from Example 8A and 43 mg (0.18 mmol) of the compound from Example 144A. 38 mg (53% of theory) of the target compound were obtained.

Example 191

3- [1- (4-chlorophenyl) -1-cyclopropylpropyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 186 starting from 84 mg (0.48 mmol) of the compound from Example 8A and 100 mg (0.48 mmol) of the compound from Example 145A. 38 mg (21% of theory) of the desired compound were obtained.

Example 192

3- [3- (4-chloro-2-fluorophenyl) pentan-3-yl] -7-[(methylsulfanyl) methyl] -1H-indole

600 mg (2.77 mmol) of the compound from Example 146A, 585 mg (2.64 mmol) of indium (III) chloride and 301 mg (2.64 mmol) of trifluoroacetic acid 446 mg (2.52 mmol) in 15 mL of dichloromethane ) Was added to the compound from Example 8A. The reaction mixture was stirred at 80 ° C. for 1 hour. After cooling to room temperature, the reaction solution was mixed with dichloromethane and silica gel and the solvent was removed on a rotary evaporator. The residue was purified twice by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient) and twice by preparative HPLC (mobile phase: acetonitrile / water gradient). 208 mg (22% of theory) of the title compound were obtained.

Example 193

3- (5,7-difluoro-4-methyl-3,4-dihydro-2H-chromen-4-yl) -7-[(methylsulfanyl) methyl] -1H-indole

565 mg (2.82 mmol) of the compound from Example 171A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 mL of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient), then flash chromatography on silica gel (mobile phase: dichloromethane). . 632 mg (62% of theory) of the title compound were obtained.

Example 194

3- (4-cyclopropyl-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl) -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 193 starting from 450 mg (2.54 mmol) of the compound from Example 8A and 574 mg (2.54 mmol) of the compound from Example 172A. 80 mg (8% of theory) of the target compound were obtained.

Example 195

2- [1- (2,4-difluorophenyl) -1- {5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [ Trans-diastereomer mixture]

273 mg (1.23 mmol) of indium (III) chloride and 0.1 ml (1.34 mmol) of trifluoroacetic acid are added to 250 mg (1.12 mmol) of the compound from Example 11A and 437 mg (2.24 mmol) of the run The compound from example 133A was introduced into 44 mL of dichloromethane and the mixture was stirred at rt overnight. The reaction mixture was concentrated on a rotary evaporator. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 313 mg (69% of theory) as a mixture of diastereomers. .

Example 196

3- [1- (4-chlorophenyl) -1-cyclopropylethyl] -7-[(methylsulfinyl) methyl] -1H-indole

131 mg (0.37 mmol) of the compound from Example 184 were introduced into 25 mL of dichloromethane at 0 ° C., 91 mg (0.37 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 113 mg (83% of theory) of the title compound as a mixture of diastereomers.

Example 197

3- {1-cyclopropyl-1- [4- (trifluoromethyl) phenyl] ethyl} -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 196 starting from 76 mg (0.20 mmol) of the compound from Example 185. 42 mg (53% of theory) of the target compound were obtained as a mixture of diastereomers.

Example 198

3- [1- (4-chlorophenyl) -1-cyclopropylpropyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 196 starting from 58 mg (0.16 mmol) of the compound from Example 191. 50 mg (82% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 199

3- (5,7-difluoro-4-methyl-3,4-dihydro-2H-chromen-4-yl) -7-[(methylsulfinyl) methyl] -1H-indole

75 mg (0.21 mmol) of the compound from Example 193 were introduced into 10 mL of dichloromethane at 0 ° C., 51 mg (0.21 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient).

Example 200

3- [5-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-yl] -7-[(methylsulfonyl) methyl] -1H-indole

64.0 mg (0.26 mmol) of 70% purity meta-chloroperbenzoic acid was added to 46.6 mg (0.13 mmol) of the compound from Example 175 in 10 mL of dichloromethane at 0 ° C. and the mixture was stirred at rt overnight. . It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 18 mg (35.5% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 201

3- (6-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfonyl) methyl] -1H-indole

64.0 mg (0.26 mmol) of 70% purity meta-chloroperbenzoic acid was added to 46.6 mg (0.13 mmol) of the compound from Example 176 in 10 mL of dichloromethane at 0 ° C. and the mixture was stirred at rt overnight. . It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 24.0 mg (47% of theory) of the diastereomer. Obtained as a mixture.

Example 202

2- (1- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} -1- [4- (trifluoromethyl) phenyl] ethyl) cyclopropanecarbonitrile [trans-diastere Isomer mixture]

8.5 mg (0.04 mmol) of 70% purity meta-chloroperbenzoic acid is added to 7.0 mg (0.02 mmol) of the compound from Example 177 in 1 mL of dichloromethane at 0 ° C. and the mixture is allowed to stand at room temperature for 1 hour. Stirred. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 4.8 mg (64% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 203

2- [1- (2,4-difluorophenyl) -1- {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

135 mg (0.55 mmol) of 70% pure meta-chloroperbenzoic acid are added to 100 mg (0.26 mmol) of the compound from Example 178 in 6 mL of dichloromethane at 0 ° C. and the mixture is kept at room temperature for 1 hour. Stirred. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 80.5 mg (74% of theory) of the title compound of the diastereomer. Obtained as a mixture.

In a similarly performed batch, an additional 25.0 mg of the title compound was obtained as a mixture of diastereomers which were combined with the first fraction.

Diastereomers and enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / (isopropanol / methanol (1: 1)) 75:25; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 203-1:

R _t = 14.37 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isopropanol / methanol (1: 1) / isohexane 25:75; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm].

Example 204

2- [1- (4-chlorophenyl) -1- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [trans-diastere Isomer mixture]

247 mg (1.00 mmol) of 70% pure meta-chloroperbenzoic acid were added to 200 mg (0.50 mmol) of the compound from Example 179 in 6 mL of dichloromethane at 0 ° C. and the mixture was stirred at rt overnight. . 2 mL of methanol was added and the residue was concentrated, then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added), 110 mg (48% of theory) The title compound of was obtained as a mixture of diastereomers.

Example 205

3- [1- (4-chlorophenyl) -1- (2,2-difluorocyclopropyl) ethyl] -7-[(methylsulfonyl) methyl] -2,3-dihydro-1H-indole

15.1 mg (0.06 mmol) of 70% pure meta-chloroperbenzoic acid was added to 12.0 mg (0.03 mmol) of the compound from Example 180 in 1 mL of dichloromethane and the mixture was stirred at rt for 2 h. Methanol was added and the residue was concentrated and then purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to 6.0 mg (46% of theory) of the title compound. Was obtained as a mixture of diastereomers.

Example 206

3- (1-ethyl-5-fluoro-2,3-dihydro-1H-inden-1-yl) -7-[(methylsulfonyl) methyl] -1H-indole

27.5 mg (0.16 mmol) of 70% purity meta-chloroperbenzoic acid was added to 27.0 mg (0.08 mmol) of the compound from Example 181 in 2 mL of dichloromethane and the mixture was stirred at rt overnight. 2 mL of methanol was added and the residue was concentrated and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid), 3.6 mg (12% of theory) The title compound of was obtained as a mixture of diastereomers.

Example 207

3- {1-cyclopropyl-1- [2-fluoro-4- (trifluoromethyl) phenyl] ethyl} -7-[(methylsulfonyl) methyl] -1H-indole

32.3 mg (0.13 mmol) of 70% purity meta-chloroperbenzoic acid was added to 26.0 mg (0.06 mmol) of the compound from Example 182 in 2 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 16 mg (57% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 208

3- [1-cyclopropyl-1- (4-methylphenyl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

151 mg (0.61 mmol) of 70% pure meta-chloroperbenzoic acid were added to 100 mg (0.30 mmol) of the compound from Example 183 in 2 mL of dichloromethane and the mixture was stirred at rt overnight. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 52.9 mg (48% of theory) as a mixture of diastereomers. .

Example 209

3- [1- (4-chlorophenyl) -1-cyclopropylethyl] -7-[(methylsulfonyl) methyl] -1H-indole

261 mg (0.74 mmol) of the compound from Example 184 were introduced into 50 mL of dichloromethane at 0 ° C., 361 mg (1.47 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed on a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 214 mg (75% of theory) of the title compound.

Example 210

3- {1-cyclopropyl-1- [4- (trifluoromethyl) phenyl] ethyl} -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 153 mg (0.39 mmol) of the compound from Example 185. 63 mg (38% of theory) of the target compound were obtained.

Example 211

3- [1-cyclopropyl-1- (3-fluoro-4-methoxyphenyl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 282 mg (0.76 mmol) of the compound from Example 186. 215 mg (70% of theory) of the desired compound were obtained.

Example 212

3- [1- (1-benzothiophen-5-yl) -1-cyclopropylethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 237 mg (0.63 mmol) of the compound from Example 187. 144 mg (56% of theory) of the desired compound were obtained.

Example 213

3- [1-cyclopropyl-1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 94 mg (0.25 mmol) of the compound from Example 188. 56 mg (55% of theory) of the desired compound were obtained.

Example 214

3- [1- (1,3-benzodioxol-5-yl) -1-cyclopropylethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 214 mg (0.59 mmol) of the compound from Example 189. 162 mg (69% of theory) of the target compound were obtained.

Example 215

3- [1-cyclopropyl-1- (2,2-difluoro-1,3-benzodioxol-5-yl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 33 mg (0.08 mmol) of the compound from Example 190. 27 mg (76% of theory) of the desired compound were obtained.

Example 216

3- [1- (4-chlorophenyl) -1-cyclopropylpropyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 116 mg (0.31 mmol) of the compound from Example 191. 98 mg (78% of theory) of the target compound were obtained.

Example 217

3- [3- (4-chloro-2-fluorophenyl) pentan-3-yl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 162 mg (0.43 mmol) of the compound from Example 192. 164 mg (93% of theory) of the desired compound were obtained.

Example 218

3- (5,7-difluoro-4-methyl-3,4-dihydro-2H-chromen-4-yl) -7-[(methylsulfonyl) methyl] -1H-indole

510 mg (1.42 mmol) of the compound from Example 193 were introduced into 50 mL of dichloromethane at 0 ° C., 700 mg (2.84 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 5 mL of methanol was added and the solution was extracted with saturated aqueous sodium bicarbonate solution. After removal of the solvent, on a rotary evaporator, the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 386 mg (70% of theory) of the title compound.

Example 219

3- (4-cyclopropyl-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl) -7-[(methylsulfonyl) methyl] -1H-indole

65 mg (0.17 mmol) of the compound from Example 194 were introduced into 10 mL of dichloromethane at 0 ° C., 83 mg (0.34 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 48 mg (68% of theory) of the title compound.

Example 220

2- [1- (2,4-difluorophenyl) -1- {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} ethyl] cyclopropanecarbonitrile [ Trans-diastereomer mixture]

63.1 mg (0.26 mmol) of 70% purity meta-chloroperbenzoic acid was added to 50.0 mg (0.13 mmol) of the compound from Example 195 in 5 mL of dichloromethane and the mixture was stirred at rt overnight. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 40.1 mg (74% of theory) of the title compound as a mixture of diastereomers. .

Example 221

3- [cyclopropyl (2,4-dichlorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

0.2 ml (2.76 mmol) of trifluoroacetic acid are added to 500 mg (2.30 mmol) of the compound from Example 147A and 408 mg (2.30 mmol) of the compound from Example 8A in 32 mL of dichloromethane and the mixture Was stirred at rt for 30 min. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 342 mg (35% of theory) of the title compound of the diastereomer. Obtained as a mixture.

Example 222

3- {cyclopropyl [2-fluoro-4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfanyl) methyl] -1H-indole

0.66 ml (8.61 mmol) of trifluoroacetic acid is added to 1.68 g (7.18 mmol) of the compound from Example 148A and 1.27 g (7.18 mmol) of the compound from Example 8A in 80 mL of dichloromethane and the mixture Was stirred at room temperature for 2 hours. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) , 80.0 mg (3% of theory) of the title compound were obtained.

Example 223

3- {cyclopropyl [4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfanyl) methyl] -1H-indole

0.76 ml (9.82 mmol) trifluoroacetic acid are added to 1.77 g (8.19 mmol) of the compound from Example 149A and 1.45 g (8.19 mmol) of the compound from Example 8A in 91 mL of dichloromethane and the mixture Was stirred at room temperature for 2 hours. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) , 890 mg (29% of theory) of the title compound were obtained.

Example 224

3-{[2-chloro-4- (trifluoromethyl) phenyl] (cyclopropyl) methyl} -7-[(methylsulfanyl) methyl] -1H-indole

2.6 ml (33.8 mmol) of trifluoroacetic acid are added to 7.07 g (28.2 mmol) of the compound from Example 150A and 5.00 g (28.2 mmol) of the compound from Example 8A in 620 mL of dichloromethane and the mixture Was stirred at room temperature for 2 hours. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene / ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) 960 mg (7% of theory) of the title compound were obtained.

Example 225

3-[(4-chloro-2-fluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

0.13 ml (1.73 mmol) trifluoroacetic acid is added to 256 mg (1.45 mmol) of the compound from Example 8A and 290 mg (1.45 mmol) of the compound from Example 151A in 20 mL of dichloromethane and the mixture Was stirred at room temperature for 2 hours. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 273 mg (51% of theory) of the title compound.

Example 226

3- [cyclopropyl (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

188 mg (1.13 mmol) of cyclopropyl (4-fluorophenyl) methanol and 0.10 ml (1.35 mmol) of trifluoroacetic acid were added to the compound from Example 8A in 200 mg (1.13 mmol) in 13 mL of dichloromethane. Added. The reaction mixture was stirred at rt for 15 min, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 267 mg (73% of theory) of the title compound were obtained.

Example 227

3-[(4-chlorophenyl) (cyclopropyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

515 mg (2.82 mmol) of the compound from Example 153A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 mL of dichloromethane. The reaction mixture was stirred at rt for 30 min, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 500 mg (50% of theory) of the title compound were obtained.

Example 228

3- [cyclopropyl (2,4-difluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 227 starting from 300 mg (1.69 mmol) of the compound from Example 8A and 312 mg (1.69 mmol) of the compound from Example 154A. 170 mg (29% of theory) of the desired compound were obtained.

Example 229

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 227 starting from 500 mg (2.82 mmol) of the compound from Example 8A and 566 mg (2.82 mmol) of the compound from Example 155A. 394 mg (39% of theory) of the desired compound were obtained.

Example 230

3-[(4-chloro-2,6-difluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

617 mg (2.82 mmol) of the compound from Example 156A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 mL of dichloromethane. The reaction mixture was stirred at rt overnight, the solvent was removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 155 mg (14% of theory) of the title compound were obtained.

Example 231

3- [cyclopropyl (2,2-difluoro-1,3-benzodioxol-5-yl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 227 starting from 500 mg (2.82 mmol) of the compound from Example 8A and 644 mg (2.82 mmol) of the compound from Example 157A. The difference is the stirring at room temperature for 45 minutes. 661 mg (60% of theory) of the desired compound were obtained.

Example 232

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -5-fluoro-7-[(methylsulfanyl) methyl] -1 H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 227 starting from 200 mg (1.02 mmol) of the compound from Example 11A and 206 mg (1.02 mmol) of the compound from Example 156A. 247 mg (64% of theory) of the desired compound were obtained.

Example 233

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -6-fluoro-7-[(methylsulfanyl) methyl] -1H-indole

514 mg (2.56 mmol) of the compound from Example 156A and 0.24 ml (3.07 mmol) trifluoroacetic acid were added to 500 mg (2.56 mmol) of the compound from Example 9A in 4 mL of dichloromethane. The reaction mixture was stirred for 30 minutes at room temperature, then the crude product was subjected to three times by preparative HPLC (mobile phase: acetonitrile / water gradient) and to flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10/1). Purification by 1 time. 404 mg (41% of theory) of the title compound were obtained.

Example 234

3-[(4-chlorophenyl) (cyclopropyl) methyl] -6-fluoro-7-[(methylsulfanyl) methyl] -1 H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 233 starting from 500 mg (2.56 mmol) of the compound from Example 9A and 468 mg (2.56 mmol) of the compound from Example 153A. 411 mg (44% of theory) of the target compound were obtained.

Example 235

3-[(4-chlorophenyl) (cyclopropyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

100 mg (0.29 mmol) of the compound from Example 227 were introduced into 15 mL of dichloromethane at 0 ° C., 72 mg (0.29 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to afford 135 mg of the title compound as a mixture of diastereomers.

Example 236

3- [cyclopropyl (2,4-difluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 235 starting from 50 mg (0.15 mmol) of the compound from Example 228. 43 mg (82% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 237

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 235 starting from 65 mg (0.18 mmol) of the compound from Example 229. 68 mg (100% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 238

3-[(4-chloro-2,6-difluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 235 starting from 150 mg (0.25 mmol) of the compound from Example 230. 75 mg (77% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 239

3- [cyclopropyl (2,2-difluoro-1,3-benzodioxol-5-yl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 235 starting from 100 mg (0.26 mmol) of the compound from Example 231. 92 mg (88% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 240

3-[(4-chlorophenyl) (cyclopropyl) methyl] -6-fluoro-7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 196 starting from 119 mg (0.33 mmol) of the compound from Example 234. The difference is that the mixture is stirred at 0 ° C. for 2 hours and then warmed to room temperature. 92 mg (74% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 241

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -6-fluoro-7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 196 starting from 115 mg (0.30 mmol) of the compound from Example 233. The difference is that the mixture is stirred at 0 ° C. for 2 hours and then warmed to room temperature. 85 mg (71% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 242

3- [cyclopropyl (2,4-dichlorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

361 mg (1.46 mmol) of 70% purity meta-chloroperbenzoic acid was added to 290 mg (0.77 mmol) of the compound from Example 221 in 43 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 205 mg (65% of theory) of the title compound.

Example 243

3- {cyclopropyl [2-fluoro-4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfonyl) methyl] -1H-indole

53.6 mg (0.22 mmol) of 70% purity meta-chloroperbenzoic acid was added to 45.0 mg (0.11 mmol) of the compound from Example 222 in 15 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 22.0 mg (45% of theory) of the title compound.

Example 244

3- {cyclopropyl [4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfonyl) methyl] -1H-indole

233 mg (0.95 mmol) of 70% purity meta-chloroperbenzoic acid was added to 187 mg (0.50 mmol) of the compound from Example 223 in 50 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 112 mg (55% of theory) of the title compound.

Example 245

3-{[2-chloro-4- (trifluoromethyl) phenyl] (cyclopropyl) methyl} -7-[(methylsulfonyl) methyl] -1H-indole

61.8 mg (0.25 mmol) of 70% purity meta-chloroperbenzoic acid was added to 54.1 mg (0.13 mmol) of the compound from Example 224 in 15 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 40.0 mg (69% of theory) of the title compound.

Example 246

3-[(4-chloro-2-fluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

250 mg (1.01 mmol) of 70% pure meta-chloroperbenzoic acid were added to 192 mg (0.53 mmol) of the compound from Example 225 in 30 mL of dichloromethane and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 123 mg (56% of theory) of the title compound.

Example 247

3-[(2-chloro-4-methylphenyl) (cyclopropyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

135 mg (0.61 mmol) of indium (III) chloride and 0.07 ml (0.92 mmol) of trifluoroacetic acid in 132 mg (0.61 mmol) of Example 86A and 100 mg (0.51 mmol) in 5 mL of dichloromethane ) Was added to the compound from Example 152A and the mixture was stirred at rt overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 29.0 mg (15% of theory) of the title compound.

Example 248

3- [cyclopropyl (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

160 mg (0.49 mmol) of the compound from Example 226 were introduced into 33 mL of dichloromethane at 0 ° C., 242 mg (0.49 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was stirred at 0 ° C. Stirred for 2 h. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 118 mg (67% of theory) of the title compound.

Example 249

3-[(4-chlorophenyl) (cyclopropyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

350 mg (1.20 mmol) of the compound from Example 227 were introduced into 40 mL of dichloromethane at 0 ° C., 505 mg (1.20 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 5 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 243 mg (63% of theory) of the title compound.

Example 250

3- [cyclopropyl (2,4-difluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 249 starting from 80 mg (0.23 mmol) of the compound from Example 228. 62 mg (66% of theory) of the target compound were obtained.

Example 251

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 249 starting from 285 mg (0.79 mmol) of the compound from Example 229. The difference is that the reaction solution is washed with saturated aqueous sodium bicarbonate solution before purification. 219 mg (71% of theory) of the desired compound were obtained.

Example 252

3-[(4-chloro-2,6-difluorophenyl) (cyclopropyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

104 mg (0.48 mmol) of the compound from Example 156A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 86A in 4 mL of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 100 mg (51% of theory) of the title compound were obtained.

Example 253

3- [cyclopropyl (2,2-difluoro-1,3-benzodioxol-5-yl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 249 starting from 500 mg (1.29 mmol) of the compound from Example 231. The difference is that the reaction solution is washed with saturated aqueous sodium bicarbonate solution before purification. 311 mg (57% of theory) of the desired compound were obtained.

Example 254

3-[(4-chlorophenyl) (cyclopropyl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1 H-indole

64 mg (0.35 mmol) of the compound from Example 153A and 0.03 ml (0.42 mmol) of trifluoroacetic acid were added to 80 mg (0.35 mmol) of the compound from Example 87A in 2.5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 110 mg (80% of theory) of the title compound were obtained.

Example 255

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1 H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 249 starting from 180 mg (0.48 mmol) of the compound from Example 232. 145 mg (74% of theory) of the desired compound were obtained.

Example 256

3-[(4-chloro-2,6-difluorophenyl) (cyclopropyl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

96 mg (0.44 mmol) of the compound from Example 156A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 3 mL of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 162 mg (86% of theory) of the title compound were obtained.

Example 257

3- [cyclopropyl (2,2-difluoro-1,3-benzodioxol-5-yl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

100 mg (0.44 mmol) of the compound from Example 157A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient). 151 mg (78% of theory) of the title compound were obtained.

Example 258

3-[(4-chlorophenyl) (cyclopropyl) methyl] -6-fluoro-7-[(methylsulfonyl) methyl] -1 H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 209 starting from 238 mg (0.66 mmol) of the compound from Example 234. 144 mg (55% of theory) of the desired compound were obtained.

Example 259

3-[(2-chloro-4-fluorophenyl) (cyclopropyl) methyl] -6-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 249 starting from 230 mg (0.61 mmol) of the compound from Example 233. The difference is that the mixture is stirred at 0 ° C. for 2 hours and then warmed to room temperature. 166 mg (66% of theory) of the desired compound were obtained.

Example 260

2-[{5-fluoro-7-[(methylsulfanyl) methyl] -1H-indol-3-yl} (4-methylphenyl) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

130 mg (0.59 mmol) of indium (III) chloride and 0.05 ml (0.64 mmol) of trifluoroacetic acid in 104 mL (0.53 mmol) of Example 11A and 100 mg (0.53 mmol) in 6 mL of dichloromethane ) Was added to the compound from Example 158A and the mixture was stirred under reflux for 1 hour. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 39.6 mg (20% of theory) as a mixture of diastereomers. .

Example 261

3-[(4-chlorophenyl) (2,2-difluorocyclopropyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

In three parallel batches, 3.08 g (13.9 mmol) of indium (III) chloride and 1.6 ml (20.9 mmol) of trifluoroacetic acid in each case of 2.54 g (11.6 in 125 mL of 1,2-dichloroethane) mmol) was added to the compound from Example 159A and 2.92 g (13.9 mmol) of the compound from Example 86A and the mixture was heated at reflux overnight. It was diluted in each case with dichloromethane and the three batches were combined and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered through diatomaceous earth and concentrated. The residue was purified by preparative SFC (ethylpyridine column; mobile phase: carbon dioxide / methanol gradient; 150 bar; 35 ° C.) to give 995 mg (7% of theory) as the mixture of diastereomers.

Enantiomers were separated by preparative HPLC on chiral [column: selector poly (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 10 μm, 250 mm × 20 mm ; Eluent: linear gradient isohexane / ethyl acetate 9: 1-> 2: 8 in 27 min; Flow rate: 25.0 ml / min; Temperature: RT; UV detection: 265 nm]. 173 mg of enantiomer 261-1 and 154 mg of enantiomer 261-2 were obtained.

Enantiomer 261-1:

R _t = 4.32 min [Column: Selector Poly (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 10 μm, 250 mm × 4.6 mm; Eluent: isohexane / ethyl acetate 6: 4; Flow rate: 2.0 ml / min; Temperature: RT; UV detection: 265 nm].

Enantiomer 261-2:

R _t = 5.11 min [Column: Selector Poly (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 10 μm, 250 mm × 4.6 mm; Eluent: isohexane / ethyl acetate 2: 8; Flow rate: 2.0 ml / min; Temperature: RT; UV detection: 265 nm].

Example 262

3-[(4-chlorophenyl) (2,2-difluorocyclopropyl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

97.1 mg (0.44 mmol) of indium (III) chloride and 0.05 ml (0.07 mmol) of trifluoroacetic acid at 80.0 mg (0.37 mmol) in 4 mL of 1,2-dichloroethane and 100 from Example 159A mg (0.44 mmol) was added to the compound from Example 87A and the mixture was heated at reflux overnight. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 6.0 mg (4% of theory) as a mixture of diastereomers. .

Example 263

2-[{5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} (4-methylphenyl) methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

3.63 g (16.4 mmol) of indium (III) chloride and 1.9 ml (24.6 mmol) of trifluoroacetic acid in 4.23 g (16.4 mmol) of Example 87A in 300 mL of 1,2-dichloroethane under argon And 2.56 g (13.7 mmol) of the compound from Example 158A, and the mixture was stirred at reflux for 4 hours. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 3.16 g (49% of theory) as a mixture of diastereomers. .

Example 264

2-[(4-methylphenyl) {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

195 mg (0.88 mmol) of indium (III) chloride and 0.11 ml (1.44 mmol) of trifluoroacetic acid were charged with 168 mg (0.80 mmol) of the compound from Example 86A and 150 mg () in 9 mL of dichloromethane under argon. 0.80 mmol) to the compound from Example 158A and the mixture was heated to reflux for 1 hour. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 100 mg (33% of theory) of the title compound as a mixture of diastereomers. .

Example 265

2-({7-[(methylsulfonyl) methyl] -1H-indol-3-yl} [4- (trifluoromethyl) phenyl] methyl) cyclopropanecarbonitrile [trans-diastereomer mixture]

1.05 g (4.75 mmol) of indium (III) chloride and 0.55 ml (7.12 mmol) trifluoroacetic acid in 954 mg (3.96 mmol) of Example 160A in 60 mL of 1,2-dichloroethane and 1.02 g (4.75 mmol) was added to the compound from Example 86A and the mixture was heated at reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 197 mg (12% of theory) as a mixture of diastereomers. .

The enantiomer was first purified by preparative HPLC [column on chiral] [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 20 ml / min; Temperature: RT; UV detection: 230 nm], followed by isocratic RP18 separation by acetonitrile / water 1: 1.

Enantiomer 265-1:

R _t = 5.54 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm].

R _t = 7.99 min [Column: Reprosil C18, 10 μm, 250 mm × 4.6 mm; Eluent: acetonitrile / water 1: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 210 nm].

Example 266

2-[(2-chloro-4-fluorophenyl) {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastere Isomer mixture]

1.62 g (7.31 mmol) of indium (III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid in an example of 80% purity of 1.89 g (6.65 mmol) in 75 mL of 1,2-dichloroethane. To compound from 87A and 1.50 g (6.65 mmol) of compound from Example 161A were added and the mixture was heated at reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative SFC HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 1.65 g (57% of theory) of the title compound as a mixture of diastereomers It was.

Enantiomers were separated by preparative HPLC on chiral [column: selector poly (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 10 μm, 250 mm × 20 mm ; Eluent: step gradient isohexane / ethyl acetate 1: 9 (15.7 min)-> 0: 100 (6 min); Flow rate: 80.0 ml / min; Temperature: RT; UV detection: 265 nm].

Enantiomer 266-1:

R _t = 3.62 min [Column: Selector Poly (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 10 μm, 250 mm × 4.6 mm; Eluent: ethyl acetate; Flow rate: 2.0 ml / min; Temperature: RT; UV detection: 265 nm].

Yield: 240 mg

Example 267

2-[(2,4-difluorophenyl) {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

96.9 mg (0.44 mmol) of indium (III) chloride and 0.06 ml (0.72 mmol) of trifluoroacetic acid in 113 mL (0.40 mmol) of 80% purity in 4 mL of dichloromethane under argon are obtained from Example 87A. And 100 mg (0.48 mmol) of the compound from Example 162A and the mixture was heated at reflux for 1 hour. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 69.0 mg (41% of theory) as a mixture of diastereomers. .

Example 268

2-[(4-chloro-2-methoxyphenyl) {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastere Isomer mixture]

104 mg (0.47 mmol) of indium (III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid in arginine at 93.0 mg (0.39 mmol) of Example 163A in 5 mL of 1,2-dichloroethane. And 121 mg (0.47 mmol) of the compound from Example 87A in 88% purity and heated the mixture at reflux for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution, then extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 35.0 mg (20% of theory) of diastereomers 1 and 31.3 mg ( 18% of theory) gave diastereomer 2 of the title compound.

Diastereomer 268-1:

Diastereomer 268-2:

Example 269

2-[(4-chloro-2-methoxyphenyl) {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture

104 mg (0.47 mmol) of indium (III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid in arginine at 93.0 mg (0.39 mmol) of Example 163A in 5 mL of 1,2-dichloroethane. And 112 mg (0.47 mmol) of the compound from Example 86A in 88% purity and heated the mixture at reflux for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution, then extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 30.5 mg (18% of theory) of diastereomers 1 and 28.0 mg ( 17% of theory) gave diastereomer 2 of the title compound.

Diastereomer 269-1:

Diastereomer 269-2:

Example 270

2-[(2,4-difluorophenyl) {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

116 mg (0.53 mmol) of indium (III) chloride and 0.07 ml (0.86 mmol) of trifluoroacetic acid in 100 mL (0.48 mmol) of compound from Example 86A and 120 mg (in 5 mL of dichloromethane under argon) 0.57 mmol) to the compound from Example 162A and the mixture was stirred at reflux for 1 hour. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 29.0 mg (15% of theory) as a mixture of diastereomers. .

Example 271

2-({5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} [2-fluoro-4- (trifluoromethyl) phenyl] methyl) cyclopropanecarbonitrile [Trans-diastereomer mixture]

1.63 g (7.35 mmol) of indium (III) chloride and 0.85 ml (11.0 mmol) of trifluoroacetic acid were added 1.59 g (6.13 mmol) of compound from Example 164A in 100 mL of 1,2-dichloroethane and 1.90. g (7.35 mmol) was added to the compound from Example 87A and the mixture was heated at reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 763 mg (27% of theory) of the diastereomer. Obtained as a mixture.

The mixture of diastereomers was separated by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to afford 91.9 mg of diastereomer 1 of the title compound.

Diastereomers 271-1:

Enantiomers were separated by preparative HPLC on chiral [column: selector poly (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 10 μm, 250 mm × 20 mm ; Eluent: step gradient isohexane / ethyl acetate 4: 6 (30 min) → 3: 7 (30 min) → 0: 100 (15 min); Flow rate: 80.0 ml / min; Temperature: RT; UV detection: 265 nm].

Enantiomer 271-1-1:

R _t = 7.14 min [Column: Selector Poly (on chiral silica gel based on N-methacryloyl-L-isoleucine 3-pentylamide), 10 μm, 250 mm × 4.6 mm; Eluent: ethyl acetate; Flow rate: 2.0 ml / min; Temperature: RT; UV detection: 265 nm].

Yield: 40.0 mg

Example 272

2-({5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} [4- (trifluoromethyl) phenyl] methyl) cyclopropanecarbonitrile [trans-diastere Isomer mixture]

33.0 mg (0.15 mmol) of indium (III) chloride and 0.02 ml (0.22 mmol) of trifluoroacetic acid in 3 mL mg (0.12 mmol) in 1 mL of 1,2-dichloroethane under argon were obtained from Example 160A. And 41.4 mg (0.15 mmol) of the compound from Example 87A in 82% purity and heated the mixture at reflux for 3 days. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 12.6 mg (23% of theory) of diastereomers 1 and 13.2 mg ( 24% of theory) gave diastereomer 2 of the title compound.

Diastereomer 272-1:

Diastereomer 272-2:

Example 273

2-[(4-chloro-2-fluorophenyl) {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastere Isomer mixture]

471 mg (2.13 mmol) of indium (III) chloride and 0.25 ml (3.19 mmol) of trifluoroacetic acid were added 400 mg (1.77 mmol) of compound from Example 165A and 483 mg (18.8 mL) in 18 mL dichloromethane under argon. 2.13 mmol) to the compound from Example 87A and the mixture was heated to reflux for 3 days. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, 0.1% formic acid added) and RP18 separation by acetonitrile / water 55:45 to give 131 mg (of theory). 17%) of diastereomer 1 of the title compound and 127 mg (17% of theory) of diastereomer 2 of the title compound were obtained.

Diastereomer 273-1:

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / (isopropanol / methanol (1: 1)) 6: 4; Flow rate: 20 ml / min; Temperature: RT; UV detection: 230 nm].

Enantiomer 273-1-2:

R _t = 7.90 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / (ethanol / methanol 1/1) 1: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm].

Yield: 44.0 mg

Diastereomer 273-2:

Example 274

2-[(4-chloro-2-fluorophenyl) {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

1.76 g (7.98 mmol) of indium (III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid in 1.50 g (6.65 mmol) of the compound from Example 165A in 69 mL of dichloromethane under argon and 1.67 g ( 7.98 mmol) to the compound from Example 86A and the mixture was heated to reflux for 3 days. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient with 0.1% formic acid added) and isocratic RP18 separation by acetonitrile / water 1: 1 to give 283 mg ( 10% of theory) gave diastereomer 1 and 145 mg (5% of theory) of diastereomer 2 of the title compound.

Diastereomer 274-1:

Diastereomer 274-2:

Example 275

2-[(2-fluoro-4-methylphenyl) {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

347 mg (1.57 mmol) of indium (III) chloride and 0.18 ml (2.35 mmol) of trifluoroacetic acid in 268 mg (1.31 mmol) of Example 166A in 10 mL of 1,2-dichloroethane under argon And 405 mg (1.57 mmol) of 88% purity to the compound from Example 87A and the mixture was heated at reflux overnight. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 358 mg (66% of theory) as the mixture of diastereomers. .

Example 276

2-[(4-chlorophenyl) {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

100. 0.25 mmol) was added to the compound from Example 86A in 53% purity and the mixture was heated at reflux for 3 days. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 41.0 mg (33% of theory) of the diastereomer. Obtained as a mixture.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / (ethanol / methanol (1: 1)) 1: 1; Flow rate: 20 ml / min; Temperature: RT; UV detection: 230 nm].

Enantiomer 276-1:

R _t = 11.19 min [Column: Daicel OD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / (ethanol / methanol (1: 1)) 1: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm].

Example 277

2-[(4-chlorophenyl) {5-fluoro-7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] cyclopropanecarbonitrile [trans-diastereomer mixture]

128 mg (0.58 mmol) of indium (III) chloride and 0.07 ml (0.87 mmol) of trifluoroacetic acid in 100 mL (0.48 mmol) of Example 167A in 5 mL of 1,2-dichloroethane under argon. And 149 mg (0.58 mmol) of the compound from Example 87A in 88% purity and the mixture was heated at reflux overnight. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) to give 130 mg (65% of theory) of the title compound as a mixture of diastereomers. .

410 mg of Diastereomer 1 of the title compound was obtained by separating the mixture of diastereomers in a similarly performed batch by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient, added 0.1% formic acid) It was.

Diastereomer 277-1:

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / (ethanol / methanol (1: 1) 1: 1; flow rate: 20 ml / min; temperature: RT; UV detection: 230 nm] The separated enantiomer was purified by preparative HPLC on achiral (RP18 column). Mobile phase: acetonitrile / water gradient, 0.1% formic acid added) to give 17.0 mg of enantiomer 277-1-1.

Enantiomer 277-1-1:

R _t = 13.48 min [Column: Daicel AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / (ethanol / methanol (1: 1)) 1: 1; Flow rate: 1.0 ml / min; Temperature: RT; UV detection: 230 nm].

Example 278

3- [bis (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

1.24 g (5.64 mmol) of 4,4'-difluorobenzohydrol and 1.25 g (5.64 mmol) of indium (III) chloride in 1.00 g (5.64 mmol) in 30 mL of toluene were obtained from Example 8A. Was added. The reaction mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, the reaction solution was mixed with ethyl acetate and the solids were filtered off. The filtrate was mixed with water, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to yield 0.53 g (25% of theory) of the title compound.

Example 279

3- [bis (4-chlorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 1.50 g (8.46 mmol) of the compound from Example 8A and 2.14 g (8.46 mmol) of 4,4'-dichlorobenzohydrol. 0.94 g (27% of theory) of the target compound were obtained.

Example 280

4-[(4-fluorophenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] benzonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 961 mg (4.23 mmol) of the compound from Example 173A. 276 mg (17% of theory) of the target compound were obtained.

Example 281

4-[(4-chlorophenyl) {7-[(methylsulfanyl) methyl] -1H-indol-3-yl} methyl] benzonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.03 g (4.23 mmol) of the compound from Example 174A. 248 mg (15% of theory) of the desired compound were obtained.

Example 282

3-[(4-chlorophenyl) (4-methoxyphenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.05 g (4.23 mmol) of the compound from Example 175A. 262 mg (15% of theory) of the desired compound were obtained.

Example 283

3-[(4-chloro-3-fluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.08 g (4.23 mmol) of the compound from Example 176A. 460 mg (26% of theory) of the target compound were obtained.

Example 284

3-[(3-chloro-4-fluorophenyl) (4-chlorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.15 g (4.23 mmol) of the compound from Example 177A. 483 mg (26% of theory) of the desired compound were obtained.

Example 285

3-[(4-chloro-2,6-difluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 490 mg (2.76 mmol) of the compound from Example 8A and 753 mg (2.76 mmol) of the compound from Example 178A. 140 mg (12% of theory) of the desired compound were obtained.

Example 286

3- [bis (4-chloro-2-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.22 g (4.23 mmol) of the compound from Example 179A. 97 mg (5% of theory) of the desired compound were obtained.

Example 287

3-[(4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.14 g (4.23 mmol) of the compound from Example 180A. 554 mg (31% of theory) of the desired compound were obtained.

Example 288

3-[(4-chloro-2-fluorophenyl) (2,4-difluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.15 g (4.23 mmol) of the compound from Example 181A. The difference is that after stirring at 80 ° C. for 2 days, 0.33 ml (4.23 mmol) of trifluoroacetic acid are added and stirred for another 16 hours. 65 mg (75% purity, 3% of theory) were obtained.

Example 289

3- [1- (4-chlorophenyl) -1- (4-fluorophenyl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 1.00 g (5.64 mmol) of the compound from Example 8A and 1.41 g (5.64 mmol) of the compound from Example 182A. The difference is only stirring for 4 hours at 80 ° C. 1.31 g (56% of theory) of the target compound were obtained.

Example 290

3- [1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 1.00 g (5.64 mmol) of the compound from Example 8A and 1.52 g (5.64 mmol) of the compound from Example 183A. 0.95 g (39% of theory) of the target compound were obtained.

Example 291

3-[(4-chlorophenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 500 mg (2.56 mmol) of the compound from Example 11A and 667 mg (2.56 mmol) of the compound from Example 81A. The difference is only stirring for 4 hours at 80 ° C. 535 mg (50% of theory) of the desired compound were obtained.

Example 292

5-fluoro-3-[(4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared similar to the synthesis of the compound from Example 278 starting from 500 mg (2.56 mmol) of the compound from Example 11A and 733 mg (2.56 mmol) of the compound from Example 82A. The difference is only stirring for 4 hours at 80 ° C. 428 mg (39% of theory) of the desired compound were obtained.

Example 293

3-[(4-chloro-2-methylphenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfanyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 278 starting from 500 mg (2.56 mmol) of the compound from Example 11A and 706 mg (2.56 mmol) of the compound from Example 83A. The difference is only stirring for 4 hours at 80 ° C. 616 mg (56% of theory) of the target compound were obtained.

Example 294 and Example 295

390 mg (1.03 mmol) of the compound from Example 278 were introduced into 40 mL of dichloromethane at 0 ° C., 507 mg (2.06 mmol) of 70% purity of meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 40 mg (10% of theory) of Example 294 as a mixture of diastereomers and 309 mg (73% of theory). Example 295 was obtained.

Example 294

3- [bis (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

Example 295

3- [bis (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

Example 296

3- [bis (4-chlorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

200 mg (0.49 mmol) of the compound from Example 279 were introduced into 20 mL of dichloromethane at 0 ° C., 120 mg (0.49 mmol) of 70% purity of meta-chloroperbenzoic acid were added and the mixture was allowed to come to room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 134 mg (65% of theory) of the title compound as a mixture of diastereomers.

Example 297

4-[(4-fluorophenyl) {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} methyl] benzonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 60 mg (0.16 mmol) of the compound from Example 280. 61 mg (98% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 298

4-[(4-chlorophenyl) {7-[(methylsulfinyl) methyl] -1H-indol-3-yl} methyl] benzonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 60 mg (0.15 mmol) of the compound from Example 281. 62 mg (99% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 299

3-[(4-chloro-3-fluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 75 mg (0.18 mmol) of the compound from Example 283. 76 mg (98% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 300

3-[(3-chloro-4-fluorophenyl) (4-chlorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 100 mg (0.23 mmol) of the compound from Example 284. 102 mg (98% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 301

3-[(4-chloro-2,6-difluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 40 mg (0.09 mmol) of the compound from Example 285. 38 mg (92% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 302 and Example 303

89 mg (0.20 mmol) of the compound from Example 286 were introduced into 10 mL of dichloromethane at 0 ° C., 86 mg (0.35 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at room temperature. Stir for 2 hours. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 46 mg (48% of theory) of Example 302 as a mixture of diastereomers and 31 mg (34% of theory). Example 303 was obtained.

Example 302

3- [bis (4-chloro-2-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

Example 303

3- [bis (4-chloro-2-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

Example 304

3-[(4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 100 mg (0.23 mmol) of the compound from Example 287. 99 mg (95% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 305 and Example 306

60 mg (75% purity, 0.10 mmol) of the compound from Example 288 were introduced into 6 mL of dichloromethane at 0 ° C. and 51 mg (0.21 mmol) of 70% purity of meta-chloroperbenzoic acid were added, The mixture was stirred at rt for 2 h. 2 mL of methanol was added and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 40 mg (83% of theory) of Example 305 as a mixture of diastereomers and 10 mg (63% purity, of theoretical 13%) of Example 306 was obtained.

Example 305

3-[(4-chloro-2-fluorophenyl) (2,4-difluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

Example 306

3-[(4-chloro-2-fluorophenyl) (2,4-difluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

Example 307

3- [1- (4-chlorophenyl) -1- (4-fluorophenyl) ethyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 300 mg (0.73 mmol) of the compound from Example 289. 193 mg (62% of theory) of the target compound were obtained as a mixture of diastereomers.

Example 308

3- [1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 300 mg (0.70 mmol) of the compound from Example 290. 258 mg (83% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 309

3-[(4-chlorophenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 100 mg (0.24 mmol) of the compound from Example 291. 102 mg (98% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 310

5-fluoro-3-[(4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 75 mg (0.18 mmol) of the compound from Example 292. 75 mg (96% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 311

5-fluoro-3-[(4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfinyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 296 starting from 120 mg (0.28 mmol) of the compound from Example 293. 114 mg (92% of theory) of the desired compound were obtained as a mixture of diastereomers.

Example 312

3- [bis (4-chlorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

680 mg (1.65 mmol) of the compound from Example 279 were introduced into 40 mL of dichloromethane at 0 ° C., 813 mg (3.30 mmol) of 70% pure meta-chloroperbenzoic acid were added and the mixture was brought to 0 ° C. Stirred for 2 h. 2 mL of methanol was added and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water gradient) to give 529 mg (72% of theory) of the title compound.

Example 313

4-[(4-fluorophenyl) {7-[(methylsulfonyl) methyl] -1H-indol-3-yl} methyl] benzonitrile

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 170 mg (0.44 mmol) of the compound from Example 280. 155 mg (84% of theory) of the desired compound were obtained.

Example 314

3-[(4-chlorophenyl) (4-methoxyphenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 150 mg (0.37 mmol) of the compound from Example 282. 130 mg (80% of theory) of the target compound were obtained.

Example 315

3-[(4-chloro-3-fluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 330 mg (0.80 mmol) of the compound from Example 283. 323 mg (91% of theory) of the desired compound were obtained.

Example 316

3-[(3-chloro-4-fluorophenyl) (4-chlorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 335 mg (0.78 mmol) of the compound from Example 284. 295 mg (82% of theory) of the desired compound were obtained.

Example 317

3-[(4-chloro-2,6-difluorophenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 60 mg (0.14 mmol) of the compound from Example 285. 58 mg (90% of theory) of the desired compound were obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / ethanol 6: 4; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 317-1:

R _t = 6.25 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 18.0 mg

Enantiomer 317-2:

R _t = 6.98 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm].

Yield: 18.0 mg

Example 318

3-[(4-chloro-2-fluorophenyl) (4-fluoro-2-methylphenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 410 mg (0.96 mmol) of the compound from Example 287. 427 mg (97% of theory) of the target compound were obtained.

Example 319

3- [1- (4-chlorophenyl) -1- (4-fluorophenyl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 900 mg (2.20 mmol) of the compound from Example 289. 939 mg (97% of theory) of the target compound were obtained.

Example 320

3- [1- (4-chloro-2-fluorophenyl) -1- (4-fluorophenyl) ethyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 600 mg (1.40 mmol) of the compound from Example 290. 589 mg (91% of theory) of the desired compound were obtained.

Example 321

3-[(4-chlorophenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 380 mg (0.92 mmol) of the compound from Example 291. 364 mg (89% of theory) of the desired compound were obtained.

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / ethanol 8: 2; Flow rate: 20 ml / min; Temperature: 24 ° C .; UV detection: 230 nm]. The separated enantiomer was purified again by preparative HPLC on achiral phase (mobile phase: acetonitrile / water gradient):

Enantiomer 321-1:

R _t = 7.14 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm];

Yield: 107 mg

Enantiomer 321-2:

R _t = 7.66 min [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 4 mm; Eluent: isohexane / ethanol 1: 1; Flow rate: 1 ml / min; Temperature: 24 ° C .; UV detection: 230 nm].

Yield: 110 mg

Example 322

5-fluoro-3-[(4-fluoro-2-methylphenyl) (4-fluorophenyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 310 mg (0.75 mmol) of the compound from Example 292. 269 mg (81% of theory) of the desired compound were obtained.

Example 323

3-[(4-chloro-2-methylphenyl) (4-fluorophenyl) methyl] -5-fluoro-7-[(methylsulfonyl) methyl] -1H-indole

The title compound was prepared analogously to the synthesis of the compound from Example 312 starting from 440 mg (1.03 mmol) of the compound from Example 293. 400 mg (85% of theory) of the target compound were obtained.

Example 324

3-{(2,2-difluorocyclopropyl) [4- (trifluoromethyl) phenyl] methyl} -7-[(methylsulfonyl) methyl] -1H-indole

2.05 g (9.27 mmol) of indium (III) chloride at 2.50 g (8.50 mmol) in Example 192A and 1.62 g (7.72 mmol) in 31 mL of 1,2-dichloroethane with reflux under argon To the compound from 86A was added and the mixture was heated at reflux for 2.5 h. An additional 2.00 g (9.04 mmol) of indium (III) chloride was added and the mixture was heated at reflux for 2 hours. Then ethyl acetate and saturated aqueous sodium bicarbonate solution were added, the phases were separated, the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1/1) and preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to give 13.0 mg (0.3% of theory). The title compound was obtained as a mixture of diastereomers.

Example 325

3-[(2,4-dichlorophenyl) (2,2-difluorocyclopropyl) methyl] -7-[(methylsulfonyl) methyl] -1H-indole

1.00 g (6.78 mmol) of the compound from Example 193A and 1.29 g (6.16 mmol) in 20 mL of 1,2-dichloroethane with 1.64 g (7.39 mmol) of indium (III) chloride refluxed under argon. To the compound from 86A was added and the mixture was heated at reflux for 1.5 h. Then ethyl acetate and saturated aqueous sodium bicarbonate solution were added, the phases were separated, the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (mobile phases: cyclohexane / ethyl acetate 2/1 and 1/1) and preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient) to give 28.0 mg of 1%) of diastereomer 1 of the title compound and 28.0 mg (1% of theory) of the diastereomer 2 of the title compound were obtained.

Diastereomer 325-1:

Enantiomers were separated by preparative HPLC on chiral [column: Daicel Chiralpak AS-H, 5 μm, 250 mm × 20 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 20 ml / min; Temperature: RT; UV detection: 230 nm]. 7.0 mg of enantiomer 325-1-1 and 7.0 mg of enantiomer 325-1-2 were obtained.

Enantiomer 325-1-1:

R _t = 7.58 min [Column: Daicel Chiralpak AS, 10 μm, 250 mm × 4.6 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: RT; UV detection: 230 nm].

Enantiomer 325-1-2:

R _t = 9.55 min [Column: Daicel Chiralpak AS, 10 μm, 250 mm × 4.6 mm; Eluent: isohexane / isopropanol 1: 1; Flow rate: 1 ml / min; Temperature: RT; UV detection: 230 nm].

Diastereomer 325-2:

B. Evaluation of Pharmacological Activity

Abbreviation:

DMEM: Dulbecco's modified Eagle Badge

DNA: deoxyribonucleic acid

FCS: Fetal Bovine Serum

HEPES: 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

PCR: polymerase chain reaction

Tris: Tris- (hydroxymethyl) methylamine

Advantageous pharmacological properties of the compounds of the present invention can be identified in the following assays:

1. In vitro cell assay measuring MR inhibitory activity and MR selectivity compared to other steroid hormone receptors

Antagonists of human mineralocorticoid receptors (MR) were identified and the activity of the compounds described herein was quantified using recombinant cell lines. The cells were originally derived from hamster ovarian epithelial cells (Chinese Hamster Ovary, CHO K1, ATCC: American Type Culture Collection, Virginia 20108 US).

An established chimeric system in which the ligand-binding domain of the human steroid hormone receptor is fused to the DNA-binding domain of yeast transcription factor GAL4 was used for the CHO K1 cell line. GAL4-steroid hormone receptor chimeras produced in this manner were co-transfected and stably expressed with reporter constructs in CHO cells.

Cloning:

To generate the GAL4-steroid hormone receptor chimera, the GAL4 DNA-binding domain (amino acids 1-147) from the vector pFC2 dbd (Stratagene) was converted to the mineralocorticoid receptor (MR, amino acids 734-985), progesterone receptor. (PR, amino acids 680-933) and the PCR-amplified ligand-binding domains of the androgen receptor (AR, amino acids 667-919) were cloned into the vector pIRES2 (Clontech). A reporter construct comprising 5 copies of the GAL4 binding site upstream of the thymidine kinase promoter was generated by the respective specific agonists aldosterone (MR), dexamethasone (GR), progesterone (PR) and dehydrotestosterone (AR). After activation and binding of the GAL4-steroid hormone receptor chimera, the expression of firefly-luciferase ( Photinus pyralis ) was induced.

Black way:

The day before the assay, MR, PR and AR cells were plated in medium (Optimem, 2.5% FCS, 2 mM glutamine, 10 mM HEPES) in 96- (or 384- or 1536-) well microtiter plates. And maintained in a cell incubator (96% humidity, 5% v / v CO ₂ , 37 ° C.). On the day of the assay, the material to be tested was taken up in the above-mentioned medium and added to the cells. About 10-30 minutes after the addition of the test substance, each specific agonist of the steroid hormone receptor was added. After 5-6 more hours of incubation, luciferase activity was measured using a video camera. The measured relative luminescence units produced sigmoidal stimulation curves as a function of material concentration. IC ₅₀ values were calculated using the GraphPad PRISM computer program (version 3.02).

Table A shows the IC ₅₀ values (MR) of representative exemplary compounds:

<Table A>

2. In Vivo Assay to Detect Cardiovascular Effects: Diuretic Investigation in Conscious Rats in Metabolic Cages

Fistar rats (250-350 g body weight) were given free access to food (Altromin) and beverages. From about 72 hours before testing, animals were fed reduced salt with 0.02% sodium chloride instead of normal food (ssniff R / MH, 10 mm, 0.02% Na, S0602-E081, sniff speddia) Only ssniff Spezialdiaten GmbH, Joest D-59494). During the test, the animals were allowed to freely access foods and drinks with reduced salt in a metabolic cage (Tecniplast Germany GmbH, Hohenpaisenberg D-82383) suitable for rats of this weight level. Was housed for 24 hours. At the start of the test, the material to be tested was administered to the animals using garbage in a volume of 0.5 ml of a suitable solvent per kg of body weight. Control animals were given only solvent. Control and material tests were performed on the same day. The control and substance administration groups consisted of 6 to 8 animals each. During the test, urine excreted from the animals was collected continuously in a collector at the bottom of the cage. The volume of urine per unit time was measured separately for each animal, and the concentrations of sodium and potassium ions excreted in urine were measured by standard methods of flame photometry. The sodium / potassium ratio was calculated from the measurements as a measure of the effect of the material. The measurement interval was typically within 8 hours after the start of the test (weekly) and 8 to 24 hours after the start of the test (nightly). In a modified test design, urine was collected and measured at 2 hour intervals during the day. To obtain a sufficient amount of urine for this purpose, the animals were given a specified amount of water through garbage at the beginning of the test and at two hour intervals thereafter.

3. DOCA / Salt Model

Deoxycorticosterone acetate (DOCA) was administered with a saline meal and one kidney was removed from the rats to induce hypertension characterized by relatively low renin levels. As a result of this endocrine hypertension (DOCA is a direct precursor of aldosterone), depending on the DOCA concentration chosen, there was kidney damage characterized by cardiac hypertrophy and further terminal organ damage, such as proteinuria and glomerulosclerosis in particular. Thus, it was possible to investigate the test substance for the presence of anti-hypertrophic effects and terminal organ-protective effects in this rat model.

Unilateral nephrectomy was performed on male Sprague-Dawley (SD) rats, approximately 8 weeks old (250-300 g body weight). To this end, rats were anesthetized with 1.5-2% isoflurane in a mixture of 66% N ₂ O and 33% O ₂ , and the flanks were excised to remove kidneys. So-called sham-operated animals with no kidneys removed were then used as control animals.

Unilaterally resected SD rats were given 1% sodium chloride in drinking water and deoxycorticosterone acetate (dissolved in sesame oil; Sigma) was injected subcutaneously between the scapula once a week (high dose: 100 mg / kg). / Week, subcutaneous; normal dose: 30 mg / kg / week, subcutaneous).

Substances for investigating protective effects in vivo were administered by garbage or via food (sniff). The day before starting the test, animals were randomized and grouped into groups of the same number of animals (usually n = 10). Drinks and food were allowed free access to animals throughout the test. The material is administered once daily via food or garbage for 4-8 weeks. Animals functioning as placebo groups were tested in the same manner, but only solvent or no food was provided.

The effectiveness of the test substance measures hemodynamic parameters [blood pressure, heart rate, muscle force (dp / dt), relaxation time (tau), maximum left ventricular pressure, left ventricular diastolic pressure (LVEDP)], and measures heart, kidney and lung , Protein excretion, RNA isolated from cardiac tissue, and then biomarkers (eg, ANP, atrial natriuretic peptide, and BNP, brain natriuretic peptide) using RT / TaqMan PCR. Determined by measuring gene expression.

Statistical analysis was performed using the Student's t-test after experimenting with variance of identity first.

4. In Vivo Assay for Detecting Anti-Minerallococticoid Activity in Conscious Dogs

The main purpose of the experiment was to investigate the effect of test compounds having anti-minerallococticoid receptor activity on aldosterone-induced sodium retention. The procedure for this is similar to the published method (Rosenthale, ME, Schneider F., Kassarich, J. & Datko, L. (1965): Determination of antialdosterone activity in normal dogs, Proc. Soc.Exp. Biol. Med., 118, 806-809].

Male or female beagles weighing between 8 and 20 kg were provided with standard food and free access to drinking water. On the day of the experiment, the dogs were fasted. Propofol (4-6 mg / kg intravenously; Propofol 1% Parke-Davis ^® , Goetheque, Germany) to obtain an aliquot of urine (as first day initial value) with a bladder catheter Anesthesia was briefly induced by

On day 2, all dogs received 0.3 mg of astonin (Astonin H, Merck, Germany), a metabolically stable aldosterone derivative at about 16.00.

The next morning (day 3), the test substance was orally administered to the dog in gelatin capsules. After 5 hours, blood was drawn from the dog to determine the plasma concentration of the material. Subsequently, brief anesthesia was again to obtain urine through the bladder catheter.

Treatment with the test substance led to an increase in the sodium-potassium ratio in the urine after 5 hours (the measurement of sodium and potassium is carried out by flame photometry). Likewise, spironolactone, which dose-dependently increased the sodium / potassium ratio in urine, served as a positive control and treatment with empty capsules served as a negative control.

Evaluation was performed by comparing the sodium / potassium ratio in urine between days 1 and 3. Alternatively, the sodium / potassium ratio between the placebo and the third day material can also be compared.

5. Chronic Myocardial Infarction Model in Conscious Rats

Male Fistula rats (weight 280-300 g; Harlan-Winkelmann) are anesthetized with 5% isoflurane in anesthesia cage and ventilated pump (ugo basile 7025 rodent, 50 strokes / min) , 7 ml) were connected by intubation and ventilated with 2% isoflurane / N ₂ O / O ₂ . Body temperature was maintained at 37-38 ° C. by a heating mat. Temgesic 0.05 mg / kg was given subcutaneously as analgesic. The chest was opened laterally between the third and fourth ribs, exposing the heart. The coronary artery of the left ventricle (LAD) was permanently ligated using closed yarn (prolene 1 meter 5-0 Ethicon1H) to pass slightly below the original point (below the left atrium). The incidence of myocardial infarction was monitored by ECG measurements (Cardioline, Remco, Italy). The chest was closed again, the muscle layer was closed with 1 meter 5/0 6951H of Ethibond excel, and the epidermis was closed with Etibond Excel 3/0 6558H. Surgical sutures were wetted with a spray dressing (eg, Nebacetin ^® N spray dressing, active ingredient: neomycin sulfate), followed by anesthesia.

One week after LAD closure, the size of myocardial infarction was estimated by ultrasound cardiac examination (Sequoia 512, Acuson). Animals were randomized and divided into individual treatment groups and controls not treated with substances. A simulated group that underwent surgical procedures only and did not perform LAD closure was included as an additional control.

Material treatment was performed over 8 weeks by garbage or by adding test compounds to food or beverages. Animals were weighed weekly and water and food consumption were measured every 14 days.

After 8 weeks of treatment, animals were anesthetized again (2% isoflurane / N ₂ O / air) and a pressure catheter (Millar SPR-320 2F) was inserted through the carotid artery into the left ventricle. There, heart rate, left ventricular pressure (LVP), left ventricular diastolic pressure (LVEDP), contractility (dp / dt) and relaxation rate (τ) were measured, and a Powerlab system (AD Instruments, ADI- PWLB-4SP) and Chart 5 software (SN 425-0586). Blood samples were then taken to measure blood levels of the substance and plasma biomarkers and the animals were killed. The heart (ventricular, septum left ventricle, right ventricle), liver, lungs and kidneys were removed and weighed.

6. Stroke-Induced Essential Hypertension Rat Model

So-called stroke-induced essential hypertension rats (SP-SHR) were administered sodium chloride, which paradoxically also caused physiological salt-induced regression of renin and angiotensin release several days later in this model. Thus, hypertension in SP-SHR animals is characterized by relatively high renin levels. As a result of ongoing hypertension, marked terminal organ damage appeared in the heart and kidneys, which was especially characterized by proteinuria and glomerulosclerosis, and overall vascular changes. Thus, in particular, stroke can progress primarily through cerebrovascular lesions (“stroke-induced”), which resulted in high mortality in untreated animals. Therefore, it is possible to investigate the test substance for blood pressure-lowering and terminal organ-protective effects in this rat model.

On the day before starting the test, approximately 10 weeks old male SP-SH rats (190-220 g body weight) were randomized and grouped into groups of the same number of animals (usually n = 12-14). Throughout the test, the drinks and foods containing sodium chloride (2% NaCl) were allowed free access to the animals. The material is administered once a day in the garbage for 6-8 weeks or via food (Sniff, Germany). The animals were tested in the same manner, but animals that served only food without solvent or with test substance served as placebo groups. In the mortality study, the test was terminated when about 50% of the placebo treated animals died.

The effect of the test substance was confirmed by measuring tail cuff and protein excretion in urine. Histopathological analyzes of the heart, kidney and brain were performed to determine the weight of the heart, kidney and lung after death and to subquantitate histological changes. Various biomarkers (eg, ANP, atrial natriuretic peptide, and BNP, brain natriuretic peptide, KIM-1, kidney-derived molecule 1, osteopontin-1) are derived from heart and kidney tissue or serum or plasma. RNA was isolated and measured by RT / TaqMan PCR.

Statistical analysis was performed using the Student's t-test after experimenting with variance of identity first.

7. CYP Suppression Assay

The inhibitory properties of the active ingredients of human cytochrome P450 (CYP) can involve a wide range of clinical effects (drug interactions) because most prescribed medications are broken down (metabolized) by these enzymes. Related to this is the CYP isoenzymes of the 1A and 2C families, CYP2D6, and almost 50% of CYP3A4. In order to exclude or minimize these possible drug interactions (drug-drug interactions, DDI), human liver microsomes (collected from various individuals) have the ability of substances to inhibit CYP1A2, CYP2C8, CYP2C9, CYP2D6 and CYP3A4 in humans. Study). This was done by measuring CYP isotype-specific metabolites formed from standard substrates such as, for example, phenacetin, amodiaquiin, diclofenac, dextromethorphan, midazolam and testosterone. Inhibitory effects are standard in the absence of test compound at six different concentrations of test compound (1.5, 3.1, 6.3, 12.5, 25 and 50 μM as maximum concentration, or 0.6, 1.3, 2.5, 5, 10 and 20 μM as maximum concentration). The substrate was investigated in comparison to CYP isotype-specific metabolite formation and the corresponding IC50 values were calculated. CYP isotype-specific standard inhibitors such as fluvoxamine, quercetin, sulfapefenazole, fluoxetine and ketoconazole served as controls for the results obtained. To obtain signs of a possible mechanism-based inhibitor (MBI) for CYP3A4, human liver microsomes were incubated for 30 minutes in the presence of an inhibitor to be examined before adding midazolam or testosterone as a standard substrate of CYP3A4. The reduction in IC50 obtained compared to the mixture without preincubation served as an indicator of mechanism-based inhibition. Mibepradil served as a positive control.

step:

Standard substrate with human liver microsomes (23-233 μg / mL) in the presence of standard compounds (as potential inhibitors) in 96-wells at workstations (Tecan, Genesis, Cralesheim, Germany) Was incubated at 37 ° C. Incubation time was 15-20 minutes. The test compound is preferably dissolved in acetonitrile (1.0 or 2.5 mM stock). 96-well plates were prepared from stocks of NADP +, EDTA, glucose 6-phosphate and glucose-6-phosphate dehydrogenase, test compounds, and phosphate buffer (pH 7.4) and phosphate buffer (pH 7.4) in phosphate buffer, pH 7.4. Prepared by sequential addition of a solution of cotton. The total volume was 200 μl. Corresponding control incubations with or without standard inhibitors were also performed in 96-well plates. After each incubation time the incubation was stopped by addition of 100 μl of acetonitrile, a suitable internal standard. Precipitated protein was removed by centrifugation (3000 rpm, 10 minutes, 10 ° C.). The resulting supernatants of each plate were combined in one plate and analyzed by LC-MS / MS. IC50 values were obtained from the generated measurement data, which were used to assess the inhibitory capacity of the test compounds.

TABLE B

8. Assay to Assess Irreversible CYP3A4 Inhibition

Cytochrome P450 enzyme inhibition, also called irreversible enzyme inhibition, also referred to as mechanism-based inhibition (MBI), is an unwanted metabolic property of a substance that can induce significant drug interactions upon simultaneous administration of other medications. The criteria for the presence of irreversible inhibition are time-, concentration- and cofactor- (nicotinamide adenine dinucleotide phosphate, NADPH) dependency inhibition. To this end, the compounds of the invention are incubated with human liver microsomes in vitro, measuring the effects on CYP3A4 activity and metabolic degradation of new active ingredients, from which the prototype parameters k _inact , K _i and the split ratio r are identified. It was.

step:

Compounds of the invention were incubated at a concentration of 2-20 μM. To this end, a stock of the active ingredient with a concentration of 0.2-2 mM was prepared in acetonitrile and then pipetted into the incubation mixture in a 1: 100 dilution multiple. Liver microsomes were incubated at 37 ° C. in 50 mM potassium phosphate buffer, pH 7.4, with or without NADPH-producing system consisting of 1 mM NADP ⁺ , 5 mM glucose 6-phosphate and 1 unit of glucose 6-phosphate dehydrogenase. After a predetermined preincubation time of 0-50 minutes, aliquots were removed from these mixtures, diluted 1:25 in a new incubation and reincubated for 20 minutes in the presence of testosterone and a new NADPH-generating system. These incubation mixtures were stopped by acetonitrile (final concentration about 30% v / v) and proteins were removed by centrifugation at about 15 000 xg. Samples stopped in this manner were either analyzed immediately or stored at −20 ° C. until analysis.

Analysis was performed by mass spectrometry detection and high performance liquid chromatography (LC-MS). Formation of 6β-hydroxytestosterone as a measure of CYP3A4 activity, and the test substance still remaining were quantified. The parameters k _inact , K _i and split ratio r were determined therefrom to evaluate new active ingredients in relation to MBI.

TABLE C

C. Exemplary Embodiments of Pharmaceutical Compositions

Compounds of the invention can be converted into pharmaceutical formulations in the following manner:

refine:

Furtherance:

100 mg of the compound of the invention, 50 mg lactose (monohydrate), 50 mg corn starch (natural), 10 mg polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Produce:

Mixtures of the compounds of the invention, lactose and starch were granulated with a 5% concentration solution of PVP in water (m / m). The granules were dried and then mixed with magnesium stearate for 5 minutes. This mixture was compressed in a conventional tablet press (see above for format of the tablet). The ground compressive force for compression is 15 kN.

Orally administrable suspensions:

Furtherance:

The compounds of the invention of 1000 mg, 1000 mg of ethanol (96%), 400 mg of Lodi gel (Rhodigel ^®, xanthan gum from said FM (FMC, Pennsylvania, United States of material)) and 99 g of water.

10 mL oral suspension corresponds to 100 mg single dose of a compound of the present invention.

Produce:

Rhodigel was suspended in ethanol and compounds of the invention were added to the suspension. Water was added with stirring. The mixture was stirred for about 6 hours until the expansion of Rhodigel was complete.

Solutions that can be administered orally:

Furtherance:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. An oral solution of 20 g corresponds to a 100 mg single dose of the compound according to the invention.

Produce:

The compound of the present invention was suspended in a mixture of polyethylene glycol and polysorbate with stirring. The stirring process was continued until the compound according to the invention was completely dissolved.

Intravenous solution:

Compounds of the invention are dissolved at concentrations below saturation solubility in physiologically acceptable solvents (eg, isotonic saline solutions, 5% glucose solutions, and / or 30% PEG 400 solutions). The solution was sterile filtered and used to fill sterile and pyrogen-free injection vessels.

Claims (17)

A compound of formula (I) and salts, solvates and solvates thereof.
<Formula I>

Where
A is -S-, -S (= O)-or -S (= O) _2- ,
R ¹ is (C ₁ -C ₄ ) -alkyl or cyclopropyl,
R ² is hydrogen, fluorine or chlorine,
R ³ is hydrogen, fluorine, chlorine or methyl,
R ⁴ is hydrogen or fluorine,
R ⁵ is a chemical formula

or

Is the flag of,
Where # is the point of attachment to the indole,
D is -CH _2- , -O-, -CH ₂ -CH ₂ -or -CH ₂ -O-,
R ⁶ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,
Wherein (C ₁ -C ₄ ) -alkyl may be substituted with one to three substituents independently selected from the group of fluorine, trifluoromethyl, hydroxy and cyano,
Wherein (C ₃ -C ₆ ) -cycloalkyl can be substituted with one to three substituents independently selected from the group of fluorine, hydroxy and cyano,
R ⁷ is hydrogen, halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl or (C ₁ -C ₄ ) -alkoxy,
R ⁸ is hydrogen, halogen, methyl or trifluoromethyl,
R ⁹ is phenyl, naphthyl or 5-10 membered heteroaryl,
Wherein phenyl, naphthyl and 5- to 10-membered heteroaryl are halogen, cyano, (C ₁ -C ₄ ) -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -May be substituted with 1 to 3 substituents independently selected from the group of alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio, or
Wherein the two substituents bonded to adjacent carbon atoms of the phenyl ring together may be represented by the formulas —O—CH ₂ —O—, —O—CHF—O—, —O—CF ₂ —O—, —O—CH ₂ —CH Form a group of ₂ -O- or -O-CF ₂ -CF ₂ -O-,
R ¹⁰ is (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl,
Wherein (C ₁ -C ₆ ) -alkyl may be substituted with 1 to 3 substituents independently selected from each other from the group of fluorine, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy and cyano and ,
Wherein (C ₃ -C ₇ ) -cycloalkyl can be substituted with one to three substituents independently selected from the group of fluorine, hydroxy and cyano,
Wherein phenyl is halogen, cyano, (C ₁ -C ₄ ) -alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy, fluoromethoxy, difluorometh May be substituted with 1 to 3 substituents independently selected from the group of oxy, trifluoromethoxy and trifluoromethylthio,
R ¹¹ is hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl. The method of claim 1,
A is -S (= O)-or -S (= O) _2- ,
R ¹ is methyl or ethyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula

Is the flag of,
Where # is the point of attachment to the indole,
R ⁹ is phenyl, naphthyl or benzothienyl,
Wherein phenyl, naphthyl and benzothienyl may be substituted with one to three substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl and methoxy, or
Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring together form a group of the formula -O-CH ₂ -O- or -O-CF ₂ -O-,
R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2 -Yl, 1-hydroxycycloprop-2-yl or phenyl,
Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, cyclopropyl, 1-cyanocycloprop-2- One and 1-hydroxycycloprop-2-yl may be substituted with one or two fluorine substituents,
Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,
R ¹¹ is hydrogen,
Compounds of formula I and salts, solvates and solvates of said salts thereof. The method of claim 1,
A is -S (= O)-or -S (= O) _2- ,
R ¹ is methyl or ethyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula

or

Is the flag of,
Where # is the point of attachment to the indole,
D is -CH ₂ -or -CH ₂ -O-,
R ⁶ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,
Wherein (C ₁ -C ₄ ) -alkyl and (C ₃ -C ₆ ) -cycloalkyl may be substituted with one or two fluorine substituents,
Wherein (C ₁ -C ₄ ) -alkyl may be substituted with a substituent selected from the group of hydroxy and cyano,
Wherein (C ₃ -C ₆ ) -cycloalkyl can be substituted with a substituent selected from the group of hydroxy and cyano,
R ⁷ is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,
R ⁸ is hydrogen, fluorine, chlorine, methyl or trifluoromethyl,
R ⁹ is phenyl, naphthyl or benzothienyl,
Wherein phenyl, naphthyl and benzothienyl may be substituted with one to three substituents independently selected from each other from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl and methoxy, or
Wherein two substituents bonded to adjacent carbon atoms of the phenyl ring together form a group of the formula -O-CH ₂ -O- or -O-CF ₂ -O-,
R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2- Dimethyleth-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1- Cyano-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate -2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1 -Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylpro Pro-3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl, (C ₃ -C ₇ ) -cycloalkyl or phenyl ego,
Wherein 1-cyanoeth-2-yl, 1-cyano-1-methyleth-2-yl, 1-cyano-2-methyleth-2-yl, 1-cyano-1,2-dimethyl Et-2-yl, 1-cyano-2,2-dimethyleth-2-yl, 1-cyanoprop-3-yl, 1-cyano-1-methylprop-3-yl, 1-cya No-2-methylprop-3-yl, 1-cyano-3-methylprop-3-yl, 1-cyano-2,3-dimethylprop-3-yl, 1-hydroxyate- 2-yl, 1-hydroxy-1-methyleth-2-yl, 1-hydroxy-2-methyleth-2-yl, 1-hydroxy-1,2-dimethyleth-2-yl, 1- Hydroxy-2,2-dimethyleth-2-yl, 1-hydroxyprop-3-yl, 1-hydroxy-1-methylprop-3-yl, 1-hydroxy-2-methylprop 3-yl, 1-hydroxy-3-methylprop-3-yl, 1-hydroxy-2,3-dimethylprop-3-yl and (C ₃ -C ₇ ) -cycloalkyl are 1 or Can be substituted with two fluorine substituents,
Wherein (C ₃ -C ₇ ) -cycloalkyl can be substituted with a substituent selected from the group of hydroxy and cyano,
Wherein phenyl may be substituted with one or two substituents independently selected from the group of fluorine, chlorine, cyano and methyl,
R ¹¹ is methyl or ethyl,
Compounds of formula I and salts, solvates and solvates of said salts thereof. The method according to claim 1 or 3,
A is -S (= O) _2- ,
R ¹ is methyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula

Is the flag of,
Where # is the point of attachment to the indole,
R ⁹ is chemical formula

Is the flag of,
Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,
R ¹² is fluorine, chlorine, methyl and trifluoromethyl,
R ¹³ is hydrogen, fluorine or chlorine,
R ¹⁴ is hydrogen, fluorine or chlorine,
R ¹⁵ is hydrogen, fluorine or chlorine,
Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,
R ¹⁰ is cyclopropyl,
Wherein cyclopropyl may be substituted with one or two fluorine substituents,
Wherein cyclopropyl may be substituted with a cyano substituent,
R ¹¹ is methyl,
Compounds of formula I and salts, solvates and solvates of said salts thereof. The method according to claim 1 or 3,
A is -S (= O) _2- ,
R ¹ is methyl or ethyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula

Is the flag of,
Where # is the point of attachment to the indole,
D is -CH _2- ,
R ⁶ is methyl, ethyl or cyclopropyl,
R ⁷ is hydrogen, fluorine, chlorine or methyl,
R ⁸ is hydrogen, fluorine or chlorine,
Compounds of formula I and salts, solvates and solvates of said salts thereof. The method according to claim 1 or 3,
A is -S (= O) _2- ,
R ¹ is methyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula

Is the flag of,
Where # is the point of attachment to the indole,
R ⁹ is chemical formula

Is the flag of,
Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,
R ¹² is fluorine, chlorine, methyl and trifluoromethyl,
R ¹³ is hydrogen, fluorine or chlorine,
R ¹⁴ is hydrogen, fluorine or chlorine,
R ¹⁵ is hydrogen, fluorine or chlorine,
Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,
R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-2-methyleth-2-yl or 1-cyanoprop-3-yl,
R ¹¹ is methyl or ethyl,
Compounds of formula I and salts, solvates and solvates of said salts thereof. The method according to claim 1 or 2,
A is -S (= O) _2- ,
R ¹ is methyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula

Is the flag of,
Where # is the point of attachment to the indole,
R ⁹ is chemical formula

Is the flag of,
Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,
R ¹² is fluorine, chlorine, methyl and trifluoromethyl,
R ¹³ is hydrogen, fluorine or chlorine,
R ¹⁴ is hydrogen, fluorine or chlorine,
R ¹⁵ is hydrogen, fluorine or chlorine,
Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,
R ¹⁰ is

Is the flag of,
Where ## is the attachment point for -CR ⁹ R ¹¹ ,
R ¹⁶ is fluorine or chlorine,
R ¹¹ is hydrogen,
Compounds of formula I and salts, solvates and solvates of said salts thereof. The method according to claim 1 or 2,
A is -S (= O) _2- ,
R ¹ is methyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula Is the flag of,
Where # is the point of attachment to the indole,
R ⁹ is phenyl or benzothienyl,
Wherein phenyl and benzothienyl may be substituted with one or two substituents independently selected from each other from the group of fluorine, chlorine, methyl and trifluoromethyl,
R ¹⁰ is 1-cyanoeth-2-yl, 1-cyano-2-methyleth-2-yl or 1-cyanoprop-3-yl,
R ¹¹ is hydrogen,
Compounds of formula I and salts, solvates and solvates of said salts thereof. The method according to claim 1 or 2,
A is -S (= O) _2- ,
R ¹ is methyl,
R ² is hydrogen or fluorine,
R ³ is hydrogen or fluorine,
R ⁴ is hydrogen,
R ⁵ is a chemical formula

Is the flag of,
Where # is the point of attachment to the indole,
R ⁹ is chemical formula

Is the flag of,
Where * is the point of attachment to -CR ¹⁰ R ¹¹ ,
R ¹² is fluorine, chlorine, methyl and trifluoromethyl,
R ¹³ is hydrogen, fluorine or chlorine,
R ¹⁴ is hydrogen, fluorine or chlorine,
R ¹⁵ is hydrogen, fluorine or chlorine,
Provided that at least one of the radicals R ¹³ , R ¹⁴ and R ¹⁵ is hydrogen,
R ¹⁰ is cyclopropyl,
Wherein cyclopropyl may be substituted with a cyano substituent, or
Wherein cyclopropyl may be substituted with one or two fluorine substituents,
R ¹¹ is hydrogen,
Compounds of formula I and salts, solvates and solvates of said salts thereof. [A] The indole derivative of formula (I-1) is reacted with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, in an inert solvent to give a compound of formula (I-2)
<Formula I-1>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ in each case have the meaning indicated in any one of claims 1 to 9.
<Formula I-2>

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ in each case have the meaning indicated in any one of claims 1 to 9), or
[B] reacting an indole derivative of formula (I-1) with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, in an inert solvent to obtain a compound of formula (I-3)
<Formula I-1>

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ in each case have the meaning indicated in any one of claims 1 to 9.
<Formula I-3>

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ in each case have the meaning indicated in any one of claims 1 to 9), or
[C] The indole derivative of the formula (II) is oxidized in an inert solvent with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, to give a compound of the formula (II-2), and then the latter is a suitable acid and / or Reacting with a compound of formula XI in the presence of a Lewis acid to give a compound of formula I-2
<Formula II>

Wherein R ¹ , R ² , R ³ and R ⁴ in each case have the meaning indicated in any one of claims 1 to 9.
<Formula II-2>

Wherein R ¹ , R ² , R ³ and R ⁴ in each case have the meaning indicated in any one of claims 1 to 9.
<Formula XI>

(Wherein R ⁵ has the meaning indicated in any one of claims 1 to 9), or
[D] The indole derivative of the formula (II) is oxidized in an inert solvent with a suitable oxidizing agent, preferably meta-chloroperbenzoic acid, to give a compound of the formula (II-3), and then the latter is a suitable acid and / or Reacting with a compound of formula XI in the presence of a Lewis acid to give a compound of formula I-3
<Formula II>

Wherein R ¹ , R ² , R ³ and R ⁴ in each case have the meaning indicated in any one of claims 1 to 9.
<Formula II-3>

Wherein R ¹ , R ² , R ³ and R ⁴ in each case have the meaning indicated in any one of claims 1 to 9.
<Formula XI>

(Wherein R ⁵ has the meaning indicated in any one of claims 1 to 9),
Where appropriate, the resulting compounds of formula (I-2) or (I-3) are separated into their enantiomers and / or diastereomers by methods known to those skilled in the art and / or (i) solvents and / or (ii) bases Or converting solvates, salts and / or solvates of the salts thereof with an acid. The compound of claim 1 for the treatment and / or prevention of a disease. The compound of formula (I) according to any one of claims 1 to 9 for use in the treatment and / or prophylaxis of aldosteroneism, hypertension, acute and chronic heart failure, sequelae of myocardial infarction, cirrhosis, renal failure and stroke. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment and / or prophylaxis of aldosteroneism, hypertension, acute and chronic heart failure, sequelae of myocardial infarction, cirrhosis, renal failure and stroke. A pharmaceutical comprising the compound according to any one of claims 1 to 9 together with an inert, nontoxic, pharmaceutically suitable excipient. A compound according to any one of claims 1 to 9, comprising: ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis (digoxin) derivatives, vasopressin antagonists, adenosine A medicament comprising together with one or more additional active ingredients selected from the group consisting of A1 antagonists, calcium sensitizers, nitrates and antithrombotic agents. The medicament according to claim 14 or 15 for the treatment and / or prophylaxis of aldosteroneism, hypertension, acute and chronic heart failure, sequelae of myocardial infarction, cirrhosis, renal failure and stroke. An aldosteroneism, hypertension, acute and chronic heart failure in humans and animals using an effective amount of one or more compounds according to any one of claims 1 to 9, or a medicament according to any one of claims 14 to 16. , Methods of treating and / or preventing myocardial infarction, cirrhosis, renal failure and stroke.